Short acting phenylalkylamine calcium channel blockers and uses thereof

ABSTRACT

The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.

BACKGROUND OF THE INVENTION

The invention relates to the use of phenylalkylamine compounds whichblock L-type calcium channels to treat cardiovascular disorders.

Calcium Channel Blockers

Calcium channel blockers (CCBs) are a chemically diverse class ofcompounds having important therapeutic value in the control of a varietyof diseases including several cardiovascular disorders, such ashypertension, angina, and cardiac arrhythmias and include aheterogeneous group of drugs that prevent or slow the entry of calciuminto cells by regulating cellular calcium channels. Calcium influxthrough these channels initiates a process of electromechanical couplingthat ultimately leads to muscle contraction. The ability to regulate theentry of calcium into cardiac and vascular smooth muscle cells is apowerful therapeutic approach to the treatment of angina andhypertension, respectively. Likewise, blocking calcium influx intocardiac tissues and conduction systems provides a useful approach tocontrol certain types of arrhythmia.

Serum Esterases

Serum esterases play an important role in the hydrolyticbiotransformation of a vast number of structurally diverse drugs. Theseenzymes are major determinants of the pharmacokinetic behavior of mosttherapeutic agents containing ester bonds. Serum esterases areclassified into three groups, A-, B-, and C-esterases, based on theirinteraction with organophosphates (De Vriese et al., Endocrinology(2004) 145, No. 11, 4997-5005). A-esterases, includingarylesterase/paraoxonase, rapidly hydrolyze organophosphates.B-esterases, including acetylcholinesterase, butyrylcholinesterase, andnonspecific carboxylesterase, are inhibited by organophosphates.C-esterases, such as acetylesterase, do not interact withorganophosphates.

Angina

Angina is a symptom of insufficient blood oxygen supply to an area ofthe heart due to an imbalance of the oxygen supply-demand ratio. Anginais usually precipitated following exertion or emotional stress insusceptible patients due to an inability of the coronary vasculature toprovide sufficient cardiac oxygen perfusion. A narrowing of the coronaryarteries is often an underlying cause as a result of arteriosclerosis orvasospastic narrowing of blood vessels. Angina usually lasts less than15 minutes and is typically treated by sublingual administration ofnitroglycerin to relieve symptoms. Nitroglycerin and other nitratesinduce vasodilation through release of nitric oxide (NO) thereby causinga lowering of blood pressure.

Angina can be classified as stable angina whose principal underlyingcause is arteriosclerosis, vasospastic angina (also called variantangina or Prinzmetal angina) whose underlying cause is due to transientvasospasm of the coronary arteries, or unstable angina cause by plateletclotting at sites of ruptured arteriosclerotic plaques. Stable anginausually occurs as a result of exertion or stress whereas vasospasticangina can also be felt during periods of rest or in the early morninghours. Unstable angina is felt even during periods of rest and cansignal imminent myocardial infarction. Sustained reduced blood flow(ischemia) to the heart can cause permanent damage to the heart due tothe death of cardiac muscle. When coronary arteries are severelynarrowed by more than 50-70%, the blood vessels can no longer supply theoxygen demands of the heart and angina is felt symptomatically as chestpain.

Cardiac Arrhythmia and Atrial Fibrillation

Arrhythmia, or abnormal heart rhythms, is caused by abnormal excitationand conduction to the heart. The mechanism of the onset of arrhythmia iscategorized into three groups: (1) abnormal excitation, (2) abnormalconduction of excitation, and (3) a combination of abnormal excitationand abnormal conduction of excitation.

Atrial fibrillation is arrhythmia arising from abnormalities in theintrinsic pacemaker conductive potential of the heart. In atrialfibrillation, the electrical discharges are rapid and irregular,resulting in an irregular rhythm of heart contraction. In a normalheart, electrical discharges are generated in the sino-atrial node. Inatrial fibrillation, electrical discharges are not generated exclusivelyin the sino-atrial node and come from other parts of the atria. Theserapid and irregular discharges result in rapid and ineffectual atrialcontractions that reduce the ability of the atria to supply blood to theventricles.

A recurrent arrhythmia with an abrupt onset and termination isdesignated as paroxysmal. Paroxysmal supraventricular tachycardia (PSVT)presents as episodes of regular and paroxysmal palpitations with suddenonset and termination (Blomstrom-Lundqvist et al., 2003, J Am CollCardiol, 42:1493-531).

Atrial flutter is characterized by acute symptoms of palpitations,dyspnea, fatigue, or chest pain. In most instances, patients with atrialflutter have a two-to-one atrio-ventricular node (AV) conductionpattern. For example, the flutter rate of the atria can be 300 perminute with a ventricular rate of 150 beats per minute(Blomstrom-Lundqvist et al., 2003, J Am Coll Cardiol, 42:1493-531).

Blood Flow and Pressure Regulation

Hypertension is defined as high blood pressure, usually above 140(systolic)/90 (diastolic). Hypertensive conditions can occur in relationto the conduction of surgical procedures. For example, blood pressurecontrol is critical before, during, and after surgery. Hypertensivecrisis arising from high blood pressure is subdivided into twocategories: urgent and emergency. The symptoms of an emergencyhypertensive crisis are more severe and may include brain swelling,stroke, pulmonary edema, heart attack or other symptoms. Both urgent andemergency categories hypertensive crisis involve a severe increase inblood pressure and require immediate treatment to prevent potentialcomplications (i.e., stroke or damage to organs and tissues).

Raynaud's phenomenon is a disorder associated with restricted blood flowto body extremities such as the fingers, toes, ears and nose, andreflects an aberration of the normal response to cold involvingperipheral vasoconstriction and restriction of blood flow to theextremities in order to protect the core body temperature. Attacks maybe brought on by exposure to cold or emotional stress. Up to 5 to 10% ofthe population of the United States is affected, to some degree, byRaynaud's phenomenon.

Intermittent claudication is a condition that involves discomfort in thelegs and occasionally the arms. It is due to a narrowing of the arteriesand a resulting decrease in blood flow, particularly to muscles duringphysical exertion. The condition most commonly occurs in the calf musclebut may also affect the foot, hip or buttocks.

No-reflow phenomenon is a condition following reperfusion in whichexcessive or abnormal vasoconstriction occurs. The no-reflow phenomenonthat occurs in about 2-5% of patients undergoing percutaneoustransluminal coronary angioplasty (PTCA) is believed to be due toaggregation of platelets and neutrophils, which causes a blockage ofblood flow within the vessels and vasoconstriction from substancesreleased from the platelets. The condition is characterized by abnormaltissue perfusion. Persistent no-reflow is associated with higherclinical complication rates (Eeckhout, E. and Kern, M. J., EuropeanHeart Journal (2001) 22, 729-739).

Given the prevalence of cardiovascular disorders in patients, there is aneed for new and improved compound and methods for treatingcardiovascular disorders including ischemic heart conditions and cardiacarrhythmias.

SUMMARY OF THE INVENTION

The invention relates to the use of a pharmaceutically effective amountof a short-acting calcium channel blocking compounds for use in treatingischemic heart conditions such as angina pectoris and cardiac arrythmiassuch as paroxysmal supraventricular tachycardia, atrial flutter andatrial fibrillation in humans. The compounds may also be used to treatother cardiovascular disorders and conditions involving hypertension andblood flow.

Accordingly, the first aspect of the invention features a method oftreating an ischemic heart condition or cardiac arrhythmia, where themethod includes administering to a patient in need thereof atherapeutically effective amount of a compound having the formula

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In some embodiments of the invention, the ischemic heart condition isstable or unstable angina or vasospastic angina. In other embodiments ofthe invention, the cardiac arrhythmia is atrial fibrillation, atrialflutter, paroxysmal supraventricular tachycardia (PSVT), prematureatrial, nodal, or ventricular depolarizations, atrial tachycardia,ventricular tachycardia, ventricular fibrillation, or Torsades dePointes.

In certain embodiments, administering includes sublingual, buccal,transdermal, intranasal or inhalation administration and the patientdesirably is a human patient.

In a second aspect, the invention features a method of treating ahypertensive crisis in an emergency room setting, where the methodincludes administering to a patient in need thereof a therapeuticallyeffective amount of a compound having the formula

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In some embodiments of the invention, administering includes sublingual,buccal, intranasal, inhalation, or parenteral administration. In certainembodiments of the invention, parenteral administration is intravenousadministration. In still other embodiments, the patient is a humanpatient.

In a third aspect, the invention features a method of treatinghypertension before, during, or after surgery, or no-reflow phenomenonfollowing reperfusion, where the method includes administering to apatient in need thereof a therapeutically effective amount of a compoundhaving the formula

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In some embodiments of the invention, administering involves parenteraladministration. In select embodiments, the parenteral administration isintravenous administration. In other embodiments of the invention, thepatient is a human patient.

The fourth aspect of the invention features another method of treating adisease associated with decreased skeletal muscle blood flow where themethod includes administering to a patient in need thereof atherapeutically effective amount of a compound having the formula

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In some embodiments, the disease associated with decreased skeletalmuscle blood flow is Raynaud's phenomenon or intermittent claudication.In other embodiments, administering includes sublingual, buccal,transdermal, intranasal, inhalation or topical administration.

In a fifth aspect, the invention features a pharmaceutical compositionincluding a compound having the following structure:

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In some embodiments, the pharmaceutical composition is formulated fortreating a condition selected from the group consisting of:

-   -   ischemic heart conditions;    -   cardiac arrhythmia;    -   hypertensive crisis in an emergency room setting;    -   hypertension before, during, or after surgery;    -   no-reflow phenomenon following reperfusion; and    -   a disease associated with decreased skeletal muscle flow.

In a sixth aspect, the invention features a kit including

-   -   (a) a pharmaceutical composition that includes a compound having        the following structure:

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₀ is, independently, H, optionally substituted lower        alkyl, or optionally substituted lower alkoxyalkyl;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently, H, halogen, optionally substituted lower alkyl,        optionally substituted lower alkoxyalkyl, or CO₂R₁₀;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃, H, or halogen; and

(b) instructions for using the pharmaceutical composition of (a) for thetreatment of a condition selected from the group consisting of:

-   -   ischemic heart conditions;    -   cardiac arrhythmia;    -   hypertensive crisis in an emergency room setting;    -   hypertension before, during, or after surgery;    -   no-reflow phenomenon following reperfusion; and    -   a disease associated with decreased skeletal muscle flow.

In a preferred embodiment of the invention,

-   -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀; and    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl.

In any of the methods, compositions, or kits of the invention, thecompound used in the invention can exclude any of the followingcompounds:

In any of the methods, compositions, or kits of the invention, thecompound used in the invention may be stereochemically pure or may beused as a mixture of stereochemical isomers. In some embodiments, thecompound is racemic. In other embodiments, the compound is a singleenantiomer or a single diastereomer. In still other embodiments, thecompound is a mixture of diastereomers or a mixture of enantiomers.

In any of the methods, compositions, or kits of the invention, preferredembodiments include a compound where:

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀;    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃ or H;

where the compound is not verapamil, gallopamil, emopamil, mepamil, ordevapamil.

In any of the methods, compositions, or kits of the invention, someembodiments include a compound where at least one of R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₇, R₁₈, and R₂₀ is CO₂R₁₀, lower alkyl substituted by—CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower alkoxyalkyl),a lower alkoxyalkyl substituted with —CO₂(lower alkyl), or loweralkoxyalkyl substituted with —CO₂(lower alkoxyalkyl). In furtherembodiments, R₁₉ is H, g is a single bond, and R₂₀ is H. In still otherembodiments, R₁₉ is H, g is a single bond, R₂₀ is CO₂R₁₀, and -d-R₁₄ and-e-R₁₅ are not both —O-(lower alkyl) or —O-(lower alkoxyalkyl).

In any of the methods, compositions, or kits of the invention, someembodiments include a compound where

-   -   (a) R₁₇ is lower alkyl;    -   (b) R₁₈ is CN or CO₂R₁₀;    -   (c) at least one of -a-R₁₁, -b-R₁₂, or -c-R₁₃ is, independently        -   (i) —O-(lower alkyl);        -   (ii) —O-(lower alkyl substituted with —CO₂(lower alkyl));        -   (iii) —O-(lower alkyl substituted with —CO₂(lower            alkoxyalkyl));        -   (iv) —O-(lower alkyl substituted with fluorine or chlorine);        -   (v) —O-(lower alkoxyalkyl);        -   (vi) —O-(lower alkoxyalkyl substituted with —CO₂(lower            alkyl));        -   (vii) —O-(lower alkoxyalkyl substituted with —CO₂(lower            alkoxyalkyl));        -   (viii) —O-(lower alkyl substituted with fluorine or            chlorine); or        -   (ix) -(single bond)-CO₂R₁₀; and    -   (d) at least one of -d-R₁₄, -e-R₁₅, -f-R₁₆, or -g-R₂₀ is,        independently,        -   (i) —O-(lower alkyl);        -   (ii) —O-(lower alkyl substituted with —CO₂(lower alkyl));        -   (iii) —O-(lower alkyl substituted with —CO₂(lower            alkoxyalkyl));        -   (iv) —O-(lower alkyl substituted with fluorine or chlorine);        -   (v) —O-(lower alkoxyalkyl);        -   (vi) —O-(lower alkoxyalkyl substituted with —CO₂(lower            alkyl));        -   (vii) —O-(lower alkoxyalkyl substituted with —CO₂(lower            alkoxyalkyl));        -   (viii) —O-(lower alkyl substituted with fluorine or            chlorine); or        -   (ix) -(single bond)-CO₂R₁₀.            In further embodiments, at least one of R₁₁, R₁₂, R₁₃, R₁₄,            R₁₅, R₁₆, R₁₇, R₁₈, or R₂₀ is CO₂R₁₀, lower alkyl            substituted by —CO₂(lower alkyl), lower alkyl substituted            with —CO₂(lower alkoxyalkyl), lower alkoxyalkyl substituted            with —CO₂(lower alkyl), or lower alkoxyalkyl substituted            with —CO₂(lower alkoxyalkyl). In further embodiments, R₁₉ is            H, g is a single bond, and R₂₀ is H. In still other            embodiments, g is a single bond, R₂₀ is CO₂R₁₀, and -d-R₁₄            and -e-R₁₅ are not both —O-(lower alkyl) or —O-(lower            alkoxyalkyl).

In any of the methods, compositions, or kits of the invention, a loweralkyl may be: methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl,i-butyl, t-butyl, pentyl, isoamyl, hexyl, heptyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, or cycloheptyl.In some embodiments, a lower alkyl is methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, or cyclopropyl.

In any of the methods, compositions, or kits of the invention, a loweralkyl substituted with —CO₂(lower alkyl) may be: —CH₂CO₂R₂₁,—CH₂CH₂CO₂R₂₁, —CH(CO₂R₂₁)CH₃, —CH₂CH₂CH₂CO₂R₂₁, —CH(CO₂R₂₁)CH₂CH₃,—CH₂CH(CO₂R₂₁)CH₃, —CH(CH₃)CH₂CO₂R₂₁, —C(CH₃)₂CO₂R₂₁,—CH₂CH₂CH₂CH₂CO₂R₂₁, —CH₂CH₂CH₂CH₂CH₂CO₂R₂₁, —CH₂CH₂CH₂CH₂CH₂CH₂CO₂R₂₁,or —CH₂CH₂CH₂CH₂CH₂CH₂CH₂CO₂R₂₁, where R₂₁ is a lower alkyl. In someembodiments, R₂₁ is methyl, ethyl, propyl, isopropyl, t-butyl, orcyclopropyl. In other embodiments, a lower alkyl substituted with—CO₂(lower alkyl) is: —CH₂CO₂CH₃, —CH₂CO₂CH₂CH₃, —CH₂CH₂CO₂CH₃, or—CH₂CH₂CO₂CH₂CH₃.

In any of the methods, compositions, or kits of the invention, a loweralkoxyalkyl may be: —CH₂OR₂₂, —CH₂CH₂OR₂₂, —CH(OR₂₂)CH₃, —CH₂CH₂CH₂OR₂₂,—CH(OR₂₂)CH₂CH₃, —CH₂CH(OR₂₂)CH₃, —CH(CH₃)CH₂OR₂₂, —C(CH₃)₂OR₂₂,—CH₂CH₂CH₂CH₂COR₂₂, —CH₂CH₂CH₂CH₂CH₂OR₂₂, —CH₂CH₂CH₂CH₂CH₂CH₂OR₂₂, or—CH₂CH₂CH₂CH₂CH₂CH₂CH(OR₂₂), where R₂₂ is a lower alkyl. In someembodiments, R₂₂ is methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,or cyclopropyl. In other embodiments, a lower alkoxyalkyl is —CH₂OCH₃,—CH₂OCH₂CH₃, —CH₂CH₂OCH₃, or —CH₂CH₂OCH₂CH₃.

In any of the methods, compositions, or kits of the invention, a loweralkyl substituted with —CO₂(lower alkoxyalkyl) may be: —CH₂CO₂R₂₃,—CH₂CH₂CO₂R₂₃, —CH(CO₂R₂₃)CH₃, —CH₂CH₂CH₂CO₂R₂₃, —CH(CO₂R₂₃)CH₂CH₃,—CH₂CH(CO₂R₂₃)CH₃, —CH(CH₃)CH₂CO₂R₂₃, —C(CH₃)₂CO₂R₂₃,—CH₂CH₂CH₂CH₂CO₂R₂₃, —CH₂CH₂CH₂CH₂CH₂CO₂R₂₃, —CH₂CH₂CH₂CH₂CH₂CH₂CO₂R₂₃,or —CH₂CH₂CH₂CH₂CH₂CH₂CH₂(CO₂R₂₃), where R₂₃ is a lower alkoxyalkyl. Insome embodiments, R₂₃ is CH₂CH₂OCH₃ or CH₂CH₂OCH₂CH₃. In otherembodiments, a lower alkyl substituted with —CO₂(lower alkoxyalkyl) is:—CH₂CO₂(CH₂CH₂OCH₃), —CH₂CO₂(CH₂CH₂OCH₂CH₃), —CH₂CH₂CO₂(CH₂CH₂OCH₃), or—CH₂CH₂CO₂(CH₂CH₂OCH₂CH₃).

In any of the methods, compositions, or kits of the invention, a loweralkyl substituted with fluorine or chlorine may be: —CH₂X, —CHX₂, —CX₃,—CH₂CX₃, —CX₂CX₃, or —CH(CX₃)₂, where X is —F or —Cl. In someembodiments, a lower alkyl substituted with fluorine or chlorine is—CF₃, —CCl₃, —CF₂CF₃, or —CH(CF₃)₂.

In any of the methods, compositions, or kits of the invention, a loweralkoxyalkyl substituted with —CO₂(lower alkyl) may be:—CH₂CH(CO₂R₂₄)OR₂₅, —CH(CO₂R₂₄)CH₂OR₂₅, —CH₂CH₂OCH₂CH₂(CO₂R₂₄), or—CH₂CH₂OCH(CO₂R₂₄)CH₃, where R₂₄ and R₂₅ are each, independently, loweralkyl. In some embodiments, R₂₄ is methyl, ethyl, propyl, isopropyl,t-butyl, or cyclopropyl. In some embodiments, R₂₅ is methyl, ethyl,propyl, isopropyl, n-butyl, t-butyl, or cyclopropyl.

In any of the methods, compositions, or kits of the invention, a loweralkoxyalkyl substituted with —CO₂(lower alkoxyalkyl) may be:—CH₂CH(CO₂R₂₆)OR₂₇, —CH(CO₂R₂₆)CH₂OR₂₇, —CH₂CH₂OCH₂CH₂(CO₂R₂₆), or—CH₂CH₂OCH(CO₂R₂₆)CH₃, where, independently, R₂₆ is a lower alkoxyalkyland R₂₇ is a lower alkyl. In some embodiments, R₂₆ is CH₂CH₂OCH₃ orCH₂CH₂OCH₂CH₃. In some embodiments, R₂₇ is methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl, or cyclopropyl.

In any of the methods, compositions, or kits of the invention, a loweralkoxyalkyl substituted with fluorine or chlorine may be:—CX₂CX₂OCH₂CH₃, —CH₂CH₂OCH₂CX₃, —CH₂CH₂OCX₂CX₃, or —CH₂CH₂OCH(CX₃)₂,where X is —F or —Cl.

In any of the methods, compositions, or kits of the invention, CO₂R₁₀may be: CO₂CH₃, CO₂CH₂CH₃, CO₂CH(CH₃)₂, CO₂C(CH₃)₃, CO₂CH₂CH₂OCH₃, orCO₂CH₂CH₂OCH₂CH₃.

In any of the methods, compositions, or kits of the invention, thecompound used in the invention desirably is any of the followingcompounds:

DEFINITIONS

The term “angina” as used herein refers to the chest discomfort felt dueto ischemic heart disease. Angina can be classified as stable anginawhose principal underlying cause is arteriosclerosis, vasospastic angina(also called variant angina or Prinzmetal angina) whose underlying causeis due to transient vasospasm of the coronary arteries, or unstableangina cause by platelet clotting at sites of ruptured arterioscleroticplaques.

As used herein, the term “buccal administration” means absorption of acompound or a pharmaceutically acceptable formulation of a compound byadministering between the cheek and gum. Desirably the compound is acompound of Formula I.

“Cardiac arrhythmia” as used herein, refers to a condition characterizedby abnormal heart rhythms that are irregular, too fast, too slow, orconducted via an abnormal electrical pathway through the heart.Arrhythmias can be divided into ventricular arrhythmias occurring in thelower chambers of the heart (ventricles) and into supraventriculararrhythmias occurring in the upper chambers of the heart (aorta).Cardiac arrhythmias include atrial fibrillation and atrial flutter thatare characterized by abnormally fast electrical discharge patterns thatcause the atria to contract very rapidly thereby impairing efficientpumping of the blood into the ventricles. Cardiac arrhythmias alsoinclude paroxysmal supraventricular tachycardia (PSVT) that ischaracterized by a regular and fast heart rate originating in hearttissue above the ventricles. Other exemplary cardiac arrhythmias arepremature atrial, nodal, or ventricular depolarization, atrialtachycardia, ventricular tachycardia, ventricular fibrillation, andTorsades de Pointes.

A “disease associated with decreased skeletal muscle blood flow” as usedherein refers to a condition where a narrowing of the arteries thatperfuse the skeletal muscle results in reduced perfusion and oxygendelivery. Such conditions include, but are not limited to, Raynaud'sphenomenon and intermittent claudication.

The term “excipient” is used herein to describe any ingredient otherthan an active compound (e.g., those having Formula I) described herein.

Excipients may include, for example: antiadherents, antioxidants,binders, coatings, compression aids, disintegrants, dyes (colors),emollients, emulsifiers, fillers (diluents), film formers or coatings,flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, or waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol,methionine, methylcellulose, methyl paraben, microcrystalline cellulose,polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinizedstarch, propyl paraben, retinyl palmitate, shellac, silicon dioxide,sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate,sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

“Hypertension before, during or after surgery” as used herein refers toperioperative hypertension, i.e., a sustained elevated blood pressure(systolic/diastolic ≧140/90 mm Hg in the USA, or ≧160/95 mm Hg in manyother countries) that occurs immediately prior to, during, or after asurgical procedure.

The term “hypertensive crisis in an emergency room setting” as usedherein refers to a sudden increase in systolic and diastolic bloodpressures that requires immediate management in a hospital or hospitalemergency room environment. The sudden acute and severe increase inblood pressure may or may not be associated with acute end-organ damage(i.e. cardiovascular, renal, central nervous system).

“Inhalation administration” or “administration by inhalation” as usedherein refers to delivering a drug for absorption to the body in theform of a liquid aerosol mist, solid aerosol particulates or a gaseoussubstance by inhalation into the lungs. Desirably the compound is acompound of Formula I.

As used herein, the term “intranasal administration” or “nasaladministration” means absorption of a compound or a pharmaceuticallyacceptable formulation of a compound by administering to the nose ornasal cavity. Desirably the compound is a compound of Formula I.

As used herein, the term “intravenous administration” means injection ofa pharmaceutically acceptable formulation of a compound directly into avein. Desirably the compound is a compound of Formula I.

The term “ischemic heart disease” or “ischemic heart condition” as usedherein refers to a condition characterized by narrowed heart arteriesthat results in restricted blood flow and reduced oxygen delivery to theheart muscle.

The term “lower alkoxyalkyl” as used herein means a lower alkyl grouphaving an ether-containing substituent such as, for example,ethoxyethyl, methoxyethyl, and methoxypropyl, among others, where theether-containing substituent may be at any position of the lower alkyl.A lower alkoxyalkyl may be, for example: —CH₂OR₂₂, —CH₂CH₂OR₂₂,—CH(OR₂₂)CH₃, —CH₂CH₂CH₂OR₂₂, —CH(OR₂₂)CH₂CH₃, —CH₂CH(OR₂₂)CH₃,—CH(CH₃)CH₂OR₂₂, —C(CH₃)₂OR₂₂, —CH₂CH₂CH₂CH₂COR₂₂, —CH₂CH₂CH₂CH₂CH₂OR₂₂,—CH₂CH₂CH₂CH₂CH₂CH₂OR₂₂, or —CH₂CH₂CH₂CH₂CH₂CH₂CH(OR₂₂), where R₂₂ is alower alkyl. Desirably, R₂₂ is methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, or cyclopropyl. Exemplary, non-limiting loweralkoxyalkyls include —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, and—CH₂CH₂OCH₂CH₃. A lower alkoxyalkyl may be optionally substituted. Asubstituted lower alkoxyalkyl may be optionally substituted, forexample, with CO₂R₁₀ at any carbon position on either the lower alkylgroup or at any carbon position on the ether containing substituent.

The term “lower alkyl” as used herein means alkyl groups of from 1 to 7carbon atoms that consist of a straight, branched or cyclicconfiguration. Lower alkyls may include 1, 2, 3, 4, 5, 6, or 7 carbonatoms. Examples of lower alkyl groups include, but are not limited to:methyl, ethyl, propyl, isopropyl, butyl, s-, i- and t-butyl, pentyl,isoamyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclobutylmethyl, and cycloheptyl, among others. Desirably,a lower alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, orcyclopropyl. A lower alkyl may be optionally substituted. A substitutedlower alkyl may be optionally substituted with, for example, CO₂R₁₀ atany carbon position.

“No-reflow phenomenon following reperfusion” as used herein refers tothe inability of myocardial tissue to reperfuse after prolonged ischemiadespite reopening of the occluded artery related to the ischemiccondition.

As used herein “parenteral administration” means administration of acompound or a pharmaceutically acceptable formulation of a compound by aroute that bypasses the gastrointestinal tract. Desirably parenteraladministration is intravenous administration, injection of apharmaceutically acceptable formulation of a compound below the skin'scutaneous layer (subcutaneous), within the dermis (intradermal), or intothe muscle (intramuscular). Desirably the compound is a compound ofFormula I.

As used herein a “pharmaceutically acceptable acid addition salt” isderived from a basic active compound and an organic acid or an inorganicacid. Exemplary pharmaceutically acceptable acid addition salts derivedfrom organic acids include, but are not limited to, acetate, adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, butyrate,camphorate, camphersulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, heptonate, hexanoate, 2-hydroxy-ethanesulfonate,isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate,maleate, malonate, methanesulfonate (mesylate), 2-naphthalenesulfonate,nicotinate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, stearate, succinate,tartrate, thiocyanate, toluenesulfonate, undecanoate, and valeratesalts, and the like. Exemplary pharmaceutically acceptable acid additionsalts derived from inorganic acids include bisulfate, sulfate, borate,hydrobromide, hydrochloride, hydroiodide, hemisulfate, nitrate,phosphate salts and the like. Desirably, a “pharmaceutically acceptableacid addition salt” is oxalate, hydrochloride, hydrobromide,methanesulfonate, sulfate, hemisulfate or bisulfate.

A “pharmaceutically acceptable carrier” as used herein refers to avehicle capable of suspending or dissolving the active compound, andhaving the properties of being nontoxic and non-inflammatory in apatient. Moreover, a pharmaceutically acceptable carrier may include apharmaceutically acceptable additive, such as a preservative,antioxidant, fragrance, emulsifier, dye, or excipient known or used inthe field of drug formulation and that does not significantly interferewith the therapeutic effectiveness of the biological activity of theactive agent, and that is non-toxic to the patient.

The term “pharmaceutically acceptable formulation” as used herein refersto a composition including a pharmaceutically acceptable carrier and anactive compound. Desirably the active compound is a compound of FormulaI.

As used herein, the term “pharmaceutical patch” refers to a padcontaining an embedded active compound to be placed on the exteriorsurface of a patient for absorption of the active compound into thebloodstream, skin or underlying tissue. Desirably, patch is placed onthe skin and the compound is released gradually from the patch overtime. Further, the patch desirably is an adhesive patch.

As used herein, the term “sublingual administration” means absorption ofa compound or a pharmaceutically acceptable formulation of a compound byadministering under the tongue. Desirably the compound is a compound ofFormula I.

As used herein, the term “therapeutically effective amount” refers to anamount of an active compound that, when administered to a patient,reduces, eliminates or prevents an ischemic heart condition, cardiacarrhythmia, hypertensive crisis in an emergency room setting,hypertension before, during or after surgery, no-reflow phenomenonfollowing reperfusion, or a disease associated with decreased skeletalmuscle bloodflow. Desirably, a therapeutically effective amount of apharmaceutical formulation contains a compound of the invention (e.g., acompound having Formula I) in a concentration range of about 0.000001 to10 percent weight/volume (“% w/v”).

“Topical administration” or “topically administering” as used hereinrefers to the application of a pharmaceutical acceptable formulation ofa compound to the external surface of a patient, such that the activecompound enters the underlying tissue. Desirably, the external surfaceis the skin and topical administration desirably involves application ofa pharmaceutically acceptable formulation to intact skin, to brokenskin, to raw skin or to an open skin wound. Desirably the compound is acompound of Formula I.

“Transdermal administration” or “transdermally administering” as usedherein refers to the diffusion of an agent across the barrier of theskin resulting from topical administration or other application of acompound or a pharmaceutically acceptable formulation of a compound.Desirably the compound is a compound of Formula I.

Where a group may be optionally substituted, optional substituentsinclude, but are not limited to: halogen (i.e., —F, —Cl, —Br, or —I),—CO₂H, —CO₂(lower alkyl), —CO₂(lower alkoxyalkyl), -(lower alkyl),-(lower alkoxyalkyl), —O(lower alkyl), —O(lower alkoxyalkyl), —NH(loweralkyl), —NH(lower alkoxyalkyl), —N(lower alkyl)₂, and —N(loweralkoxyalkyl)₂.

These definitions and others stated in The Merck Manual 16^(th) edition1992 (Chapter 25. pp 461-498; Chapter 25, pp 498-507; and Chapter 24, pp413-429) and Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” 11^(th) edition 2006 (Chapter 34, pp 899-908; Chapter 31,pp 823-824 and pp 830-832; and Chapter 32, pp 845-846) are hereinincorporated by reference in these definitions.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description and the Claims.

DETAILED DESCRIPTION

The present invention relates to the use of a pharmaceutically effectiveamount of a short-acting calcium channel blocking compound to treatischemic heart conditions, cardiac arrhythmias, hypertensive crisis inan emergency room setting, hypertension before, during, or aftersurgery, no-reflow phenomenon following reperfusion, and diseasesassociated with decreased skeletal muscle blood flow. The compounds usedin the compositions, kits, and methods of the present invention arerendered short-acting by covalent attachment of esterase sensitivegroups to molecules derived from the phenylalkylamine (e.g., verapamil)class of calcium channel blockers and may be formulated for sublingual,buccal, transdermal, intranasal, inhalation, topical, and parenteral(e.g., intravenous) routes of administration. Pharmaceuticalcompositions containing the compounds disclosed herein may be includedin a kit with instructions for administration according to the methodsof the invention.

In the context of this invention, a short acting calcium channelblocking compound is meant to infer a compound that produces the desiredeffect and is then rapidly inactivated metabolically. A short acting CCBis meant to have a duration of action of from less than 1 minute to lessthan 60 minutes. Preferably the compound's duration of action will befrom 1 minute to 30 minutes.

In desirable embodiments, the compounds used in the methods of thepresent invention are defined structurally in Formula I

or a pharmaceutically acceptable addition salt thereof, or anyenantiomer or diastereomer thereof, where the compounds represented byFormula I are further defined as follows:

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀;    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃ or H.

The compounds defined by Formula I may exist as free bases or aspharmaceutically acceptable acid addition salts.

As described above, the short-acting calcium channel blockers of theinvention (e.g., the compounds defined by Formula I) may be used totreat disorders in which the regulation of calcium plays a role innormal hemostasis. Such disorders include, for example, pulmonaryhypertension, peripheral vascular disease, mild congestive heartfailure, hypertrophic subaortic stenosis, protection against ischemicinjury, stroke, migraine, tumor resistance to anti-neoplastic drugs,achalasia, esophageal spasms, bronchial asthma, premature labor,dysmenorrhea, and enhancement of success in renal transplantation.

Pharmaceutical agents, such as a calcium channel-blocking compound, canbe made with relatively short durations of therapeutic action, rangingfrom the ultra-short to medium-range, through non-hepatic means ofinactivation. Such agents may be subject to extensive metabolism inblood by serum esterases, as well as potential metabolism in the liver.Rapid elimination or biotransformation to inactive or less activeproducts minimizes accumulation with prolonged or repeatedadministration. A calcium channel-blocking compound that is renderedsensitive to serum esterases is expected to undergo rapid degradation toinactive or less active metabolites in the blood. This may be consideredanalogous to the rapid degradation experienced by succinylcholine(Stanski, D. R. and Hug, C. C., Jr. Anesthesiology 57: 435-438 (1982))and enables a more predictable correlation of dose with the duration ofpharmacologic effect.

Anti-anginal drugs relieve or prevent coronary ischemia by increasingoxygen supply to the heart or by decreasing myocardial oxygen demand.There are three main classes of pharmaceutical agents that are used totreat angina (organic nitrates, calcium channel blockers, andbeta-adrenergic antagonists also known as beta-blockers). Organicnitrates (e.g., glyceryl trinitrate, nitroglycerin) are generallyeffective agents for treating angina and cause vasodilation throughrelease of nitric oxide (NO) to coronary arteries and coronary smoothmuscle. However, a major limitation of the use of organic nitrates isthe development of nitrate tolerance. Calcium channel blockers (e.g.,verapamil, nicardipine, nifedipine, clevidipine, diltiazem, bepredil)antagonize calcium channels in arteriole smooth muscle and cardiacmuscle resulting in vasodilation and/or reduced cardiac contractility.Calcium channel blockers are generally well tolerated with minor adverseeffects including hypotension, dizziness, edema, nausea, and vomiting,and are contraindicated for patients with hypertrophic obstructivecardiomyopathies.

Medications used to treat atrial fibrillation and slow down the abnormaland rapid heart rate include calcium channel blockers (e.g., verapamil,diltiazem), digoxin (e.g., digitalis), and beta-blockers (e.g.,propranolol, atenolol, esmolol). These pharmaceutical agents slow theheart rate by retarding conduction of the electrical discharges throughthe atrio-ventricular node, but do not usually convert atrialfibrillation back into a normal rhythm. Other drugs or treatments arenecessary to achieve a normal heart rhythm but these are generallyassociated with greater toxicity.

Calcium channel blockers and beta-blockers are often prescribed foracute pharmacological treatment of atrial flutter as well as traditionalantiarrhythmic medications such as amiodarone.

Nitrate containing drugs, such as nitroglycerin or sodium nitroprusside,can be used to address these disorders involving blood flow and pressureregulation, but these drugs can produce rebound tachycardia and otheradverse effects. Other traditional hypotensive agents, such as thecalcium channel blocker nicardipine, are generally too long acting toeffectively address blood pressure regulation surrounding surgery. Incontrast, the compounds of the invention are short acting and thusovercome the undesirable characteristics and effects noted above inconnection with existing therapies for cardiovascular disorders.

Pharmaceutical Formulations

Desirable routes of administration of the compounds (e.g., the compoundshaving Formula I) used in the present invention include sublingual,buccal, transdermal, intranasal, inhalation, topical, and parenteral(e.g., intravenous) administration. The compounds desirably areadministered with a pharmaceutically acceptable carrier. Pharmaceuticalformulations of the compounds described herein formulated for treatmentof the disorders described herein are also part of the presentinvention.

For a transdermal delivery system, the administration of a therapeuticdose will, of course, be continuous rather than intermittent throughoutthe dosage regimen.

Dosages for buccal or sublingual administration typically are 0.1 to 500mg per single dose as required. In practice, the physician determinesthe actual dosing regimen which is most suitable for an individualpatient, and the dosage varies with the age, weight, and response of theparticular patient. The above dosages are exemplary of the average case,but individual instances exist wherein higher or lower dosages aremerited, and such are within the scope of this invention.

For buccal administration, the compositions may take the form oftablets, lozenges, etc. formulated in a conventional manner. Liquid drugformulations suitable for use with nebulizers and liquid spray devicesand electrohydrodynamic (EHD) aerosol devices will typically include acompound of the invention with a pharmaceutically acceptable carrier.Preferably, the pharmaceutically acceptable carrier is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of compounds of the invention. Desirably, thismaterial is liquid such as an alcohol, glycol, polyglycol or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart (see, e.g., Biesalski, U.S. Pat. No. 5,112,598 and Biesalski, U.S.Pat. No. 5,556,611, each of which is herein incorporated by reference).

The compounds may also be formulated for nasal administration. For nasaladministration, the solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the case of a dropper or pipette, dosing may be achieved by thepatient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved,for example, by means of a metering atomizing spray pump.

The compounds may further be formulated for aerosol administration,particularly to the respiratory tract by inhalation and includingintranasal administration. The compound will generally have a smallparticle size for example on the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve.

Alternatively the active ingredients may be provided in a form of a drypowder, for example, a powder mix of the compound in a suitable powderbase such as lactose, starch, and starch derivatives such ashydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP). Thepowder carrier will form a gel in the nasal cavity. The powdercomposition may be presented in unit dose form for example in capsulesor cartridges of e.g., gelatin or blister packs from which the powdermay be administered by means of an inhaler.

For human use, a compound of the invention can be administered alone,but generally is administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. Pharmaceutical compositions for use inaccordance with the present invention thus can be formulated in aconventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries that facilitateprocessing of compounds of Formula I into preparations which can be usedpharmaceutically.

These pharmaceutical compositions can be manufactured in a conventionalmanner, e.g., by conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Proper formulation is dependent upon the routeof administration chosen. The formulation and preparation of suchcompositions is well-known to those skilled in the art of pharmaceuticalformulation.

For administration by inhalation, compounds of in the invention areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant.In the case of a pressurized aerosol, the dosage unit can be determinedby providing a valve to deliver a metered amount.

The pharmaceutical formulation may also be administered parenterally(intravenous, intramuscular, subcutaneous or the like) in dosage formsor formulations containing conventional, non-toxic pharmaceuticallyacceptable carriers and adjuvants. In particular, formulations suitablefor parenteral administration include aqueous and non-aqueous sterileinjection solutions which may contain anti-oxidants, buffers,bacteriostats and solutes which render the formulation isotonic with theblood of the intended recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.For example, to prepare such a composition, the compounds of theinvention may be dissolved or suspended in a parenterally acceptableliquid vehicle. Among acceptable vehicles and solvents that may beemployed are water, water adjusted to a suitable pH by addition of anappropriate amount of hydrochloric acid, sodium hydroxide or a suitablebuffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloridesolution. The aqueous formulation may also contain one or morepreservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate.

The formulations for parenteral administration may be presented inunit-dose or multi-dose containers, for example, sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionsrequiring only the addition of the sterile liquid carrier, for example,water for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Topical Pharmaceutical Formulations

Pharmaceutically acceptable topical formulations for use in accordancewith the present invention can be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries that facilitate processing of the compoundsof the invention (e.g., a compound of Formula I) into preparations thatcan be used pharmaceutically. Proper formulation is dependent upon thedesired product chosen. Non-limiting exemplary formulations are providedbelow.

The topical formulations useful in the subject invention can be madeinto a wide variety of product types. These include, but are not limitedto, lotions, creams, gels, sticks, sprays, ointments, pastes, mousses,and cosmetics. The product types can include several types of carriersystems including, but not limited to solutions, emulsions, gels,solids, and liposomes. Techniques for formulation and administration arestandard in the art and can be found, for example, in “Remington: TheScience and Practice of Pharmacy 20^(th) edition” Lippincott Williams &Wilkins, Philadelphia, Pa. Eds Gennaro A. R. et al, 2000. Theformulation can be selected to maximize delivery to a desired targetsite in the body such as the skin.

Lotions, which are preparations that are to be applied to the skinsurface without friction, are typically liquid or semi-liquidpreparations. Lotions may be formulated with an aqueous or oily base andwill in general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Creams containing the active agent for delivery according to the presentinvention are viscous liquid or semisolid emulsions, either oil-in-wateror water-in-oil. Cream bases are water-washable, and contain an oilphase, an emulsifier and an aqueous phase. The oil phase, also sometimescalled the “internal” phase, generally contains petrolatum and a fattyalcohol such as cetyl or stearyl alcohol; the aqueous phase usually,although not necessarily, exceeds the oil phase in volume, and generallycontains a humectant. The emulsifier in a cream formulation, asdescribed in “Remington: The Science and Practice of Pharmacy 20^(th)edition” Lippincott Williams & Wilkins, Philadelphia, Pa. Eds Gennaro A.R. et al, 2000, is generally a nonionic, anionic, cationic or amphotericsurfactant.

Gel formulations can also be used in connection with the presentinvention. As is appreciated by those working in the field of topicaldrug formulation, gels are semisolid, suspension-type systems.Single-phase gels contain organic macromolecules distributedsubstantially uniformly throughout the carrier liquid, which istypically aqueous, but also, preferably, contain an alcohol and,optionally, an oil.

Ointments, which are semisolid preparations, are typically based onpetrolatum or other petroleum derivatives. As is appreciated by theordinarily skilled artisan, the specific ointment base to be used is onethat provides for optimum delivery for the active agent chosen for agiven formulation, and, preferably, provides for other desiredcharacteristics as well, e.g., emolliency or the like. As with othercarriers or vehicles, an ointment base should be inert, stable,nonirritating and non-sensitizing. As described, for example, inRemington: The Science and Practice of Pharmacy 20^(th) edition”Lippincott Williams & Wilkins, Philadelphia, Pa. Eds Gennaro A. R. etal, 2000, at pages 845-849, ointment bases may be grouped in fourclasses: oleaginous bases; absorption bases; water-removable bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Absorption bases, also known as emulsifiableointment bases, contain little or no water and include, for example,hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.Absorption bases are either water-in-oil (W/O) emulsions or oil-in-water(O/W) emulsions, and include, for example, cetyl alcohol, glycerylmonostearate, lanolin and stearic acid. Preferred water-soluble ointmentbases are prepared from polyethylene glycols of varying molecularweight.

Useful formulations of the invention also encompass sprays. Spraysgenerally provide the active agent in an aqueous and/or alcoholicsolution which can be misted onto the skin for delivery. Such spraysinclude those formulated to provide for concentration of the activeagent solution at the site of administration following delivery, e.g.,the spray solution can be primarily composed of alcohol or other likevolatile liquid in which the drug or active agent can be dissolved. Upondelivery to the skin, the carrier evaporates, leaving concentratedactive agent at the site of administration.

A topical pharmaceutical formulation for use in the present inventionmay also include suitable solid or gel phase carriers. Examples of suchcarriers include, but are not limited to, calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

Further, a topical pharmaceutical formulation may include a suitableemulsifier, i.e., an agent that enhances or facilitates mixing andsuspending oil-in-water or water-in-oil. An emulsifying agent for use inthe invention may consist of a single emulsifying agent or may be ablend of emulsifying agents and may be a nonionic, anionic or cationicsurfactant or a blend of two or more such surfactants. Suchsurface-active agents are described, for example, in “McCutcheon'sDetergent and Emulsifiers,” North American Edition, 1980 Annualpublished by the McCutcheon Division, MC Publishing Company, 175 RockRoad, Glen Rock, N.J. 07452, USA.

Especially suitable nonionic emulsifying agents for inclusion in thepharmaceutically acceptable formulations for use in the presentinvention are those with a hydrophile-lipophile balance (HLB) asdetermined by the method described, for example, by Paul L. Lindner in“Emulsions and Emulsion”, edited by Kenneth Lissant, published byDekker, New York, N.Y., 1974, pages 188-190. Examples of such nonionicemulsifiers include, but are not limited to, “BRIJ 72,” the trade namefor a polyoxyethylene (2) stearyl ether having an HLB of 4.9; “BRIJ721,” the trade name for a polyoxyethylene (21) stearyl ether having anHLB of 15.5.

A topical pharmaceutical formulation may also contain suitableemollients. Emollients are materials that may be used for the preventionor relief of dryness, as well as for the protection of the skin. Usefulemollients include, but are not limited to, cetyl alcohol, isopropylmyristate, stearyl alcohol, and the like. A wide variety of suitableemollients are known in the art and can be used in the formulationsencompassed by the invention. See e.g., Sagarin, Cosmetics, Science andTechnology, 2nd Edition, Vol. 1, pp. 32-43 (1972), and U.S. Pat. No.4,919,934, to Deckner et al., issued Apr. 24, 1990, both of which areincorporated herein by reference in their entirety.

A topical pharmaceutical formulation for use in the methods of theinvention may also include suitable antioxidants, i.e., substances thatinhibit oxidation. Antioxidants suitable for use in accordance with thepresent invention include, but are not limited to, butylatedhydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate,ascorbic palmitate, butylated hydroxyanisole,2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol,erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid,dilauryl thiodipropionate, tert-butylhydroquinone and tocopherols suchas vitamin E, and the like, including pharmaceutically acceptable saltsand esters of these compounds. Preferably, the antioxidant is butylatedhydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid,pharmaceutically acceptable salts or esters thereof, or mixturesthereof. Most preferably, the antioxidant is butylated hydroxytoluene.

Moreover, topical pharmaceutical formulations for use in the presentinvention may also include suitable preservatives. Preservatives arecompounds added to a pharmaceutical formulation to act as ananti-microbial agent. Among preservatives known in the art as beingeffective and acceptable in parenteral formulations are benzalkoniumchloride, benzethonium, chlorohexidine, phenol, m-cresol, benzylalcohol, methylparaben, propylparaben, chlorobutanol, o-cresol,p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoicacid, and various mixtures thereof. See, e.g., Wallhausser, K.-H.,Develop. Biol. Standard, 24:9-28 (1974) (S. Krager, Basel).

A topical pharmaceutical formulation for use in the present inventionmay further contain suitable chelating agents to form complexes withmetal cations which do not cross a lipid bilayer. Examples of suitablechelating agents include ethylene diamine tetraacetic acid (EDTA),ethylene glycol-bis(beta-aminoethyl ether)-N,N,N′,N′-tetraacetic acid(EGTA) and8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N′,N′-tetraaceticacid, tetrapotassium salt (QUIN-2).

Topical pharmaceutical formulations useful for the methods of theinvention may also include suitable neutralizing agents used to adjustthe pH of the formulation to within a pharmaceutically acceptable range.For topical formulations, pH range desirably is 4.5-7.1. Most desirably,the pH range is 4.5-6.5.

Further, a topical pharmaceutical formulation may include suitablehydrophilic gelling agents. These components are, for example,diffusable compounds capable of increasing the viscosity of apolymer-containing solution through the interaction of the agent withthe polymer. Also useful herein are hydrophilic gelling agents such asthe acrylic acid/ethyl acrylate copolymers and the carboxyvinyl polymerssold by the B. F. Goodrich Company under the trademark of Carbopol®resins. These resins consist essentially of a colloidally water-solublepolyalkenyl polyether crosslinked polymer of acrylic acid crosslinkedwith from 0.75% to 2.00% of a crosslinking agent such as polyallylsucrose or polyally pentaerythritol. A desirable viscosity increasingagent is for example Carbopol® Ultrez 10.

A topical pharmaceutical formulation may also contain one or moresuitable solvents. Suitable solvents include ethanol, propylene glycol,glycerin, dipropylene glycol and polyethylene glycol. Non-lipophilicdrugs typically display very low solubility in pharmaceuticallyacceptable solvents and/or carriers.

In addition, a topical pharmaceutical formulation for use in the presentinvention may include one or more suitable skin penetration enhancers.Suitable excipients are known in the art to be skin penetrationenhancers (as described, for example, in Osborne D. W. and Henke J. J.,“Skin penetration enhancers cited in the technical literature” Pharm.Tech. 21:58-66, 1997). Examples of skin penetration enhancers includewater, ethanol, propylene glycol, oleic acid, oleyl alcohol, sodiumlauryl sulfate, dimethylsulfoxide, 1-dodecylazacycloheptan-2-one (tradename Azone®), N-methyl-2-pyrolidinone, 2-pyrolidinone, D-limonene,1,8-cineole, urea, and menthol are just a few of the known penetrationenhancers. Diethylene glycol monoethyl ether NF (CAS number 111-90-0,INCI name ethoxydiglycol, trade name TRANSCUTOL®) (see, for example,Watkinson A. C. et al., “Aspects of the transdermal delivery ofprostaglandins,” Int. J Pharm. 74:229-236, 1991; Rojas J. et al.,“Optimization of binary and ternary solvent systems in the percutaneousabsorption of morphine base,” STP Pharma Sciences, 1:70-75, 1991;Watkinson A. C., Ph.D. Thesis, University of Wales, 1991; Ritschel W. A.et al., “Development of an intracutaneous depot for drugs. Binding, drugaccumulation and retention studies,” Skin Pharmacol. 4:235-245, 1991).

Diethylene glycol monoethyl ether NF (DGME) is a useful solvent for manydrugs, especially non-lipophilic drugs having very low water solubility.In vitro skin absorption studies have shown increased flux values forcompounds dissolved in DGME; however, DGME does not fluidize the stratumcorneum lipids (Harrison J. E. et al., “The relative effect of Azone andTranscutol on permeant diffusivity and solubility in human stratumcorneum,” Pharm. Res., 13:542-546, 1996), nor does DGME decrease the lagtime associated with the permeant (Rojas J. et al., “Optimization ofbinary and ternary solvent systems in the percutaneous absorption ofmorphine base,” STP Pharma Sciences, 1:70-75, 1991). These additionalpenetration-enhancing compounds can be used when desired in thepharmaceutical compositions described herein in the conventional rangeof from about 0.1 to about 10% and preferably about 1.0% to about 5.0%by weight of the topical composition.

Liquid forms, such as lotions suitable for topical administration orsuitable for cosmetic application, may include a suitable aqueous ornon-aqueous vehicle with buffers, suspending and dispensing agents,thickeners, penetration enhancers, and the like. Solid forms such ascreams or pastes or the like may include, for example, any of thefollowing ingredients, water, oil, alcohol or grease as a substrate withsurfactant, polymers such as polyethylene glycol, thickeners, solids andthe like. Liquid or solid formulations may include enhanced deliverytechnologies such as liposomes, microsomes, microsponges, patches, andthe like.

Topical Administration

The compounds for use in the invention (e.g., compounds of Formula I)can be administered in a pharmaceutically acceptable topical (e.g.,transdermal) formulation. Topical treatment regimens according to thepractice of the invention may include applying the composition directlyto the skin at the application site, from one to several times daily.Also included are delivery methods in the form of pharmaceuticalpatches.

These formulations may include a pharmaceutically acceptable carriersuch as water, oils (including vegetable and mineral oils), cream bases,lotion bases, ointment bases, and the like. These bases includesuspending agents, thickeners, penetration enhancers, and the like.Topical and transdermal formulations are well known to those in the artof cosmetics and topical pharmaceuticals and are described, for example,in Chapter 44 of “Remington: The Science and Practice of Pharmacy20^(th) edition” Lippincott Williams & Wilkins, Philadelphia, Pa. EdsGennaro A. R. et al, 2000, which is incorporated herein by reference.

Topical (e.g., transdermal) formulations may also includepharmaceutically acceptable vehicles. Additives for topical formulationsare well-known in the art, and may be added to the topical composition,as long as they are pharmaceutically acceptable and not deleterious tothe epithelial cells or their function. Further, the additives shouldnot cause deterioration in the stability of the formulation, inparticular, of the active compound. For example, inert fillers,anti-irritants, tackifiers, excipients, fragrances, opacifiers,antioxidants, gelling agents, stabilizers, surfactants, emollients,coloring agents, preservatives, buffering agents, other permeationenhancers, and other conventional components of transdermal deliverydevices as are known in the art. Excipients generally are carriers,diluents and/or vehicles used in formulating drug compositions.Excipients are standard in the art and examples of excipients and theirapplication can be found, for instance, in Katz, M. (Drug Design4:93-148, 1973).

Penetration or permeation through the skin of an active compound may beenhanced by an agent (e.g., p20 solvents) or a mixture of agents which,alone or in combination, act to increase the permeability of the skin toa drug. The enhanced permeation effected through the use of suchenhancers can be observed, for example, by measuring the rate ofdiffusion of the drug through animal or human skin using a diffusioncell apparatus. A diffusion cell is described by Merritt et al.“Diffusion Apparatus for Skin Penetration,” J. of Controlled Release,1:161-162, 1984. Topical administration of a pharmaceutical agent canresult in a limited distribution of the agent to the skin andsurrounding tissues or, when the agent is removed from the treatmentarea by the bloodstream, can result in systemic distribution of theagent. However, transdermal administration desirably results in thediffusion of an agent across the barrier of the skin resulting fromtopical administration or other application of a pharmaceuticallyacceptable formulation. The stratum corneum acts as a barrier and fewpharmaceutical agents are able to penetrate intact skin. In contrast,the epidermis and dermis are permeable to many solutes and absorption ofdrugs therefore occurs more readily through skin that is abraded orotherwise stripped of the stratum corneum to expose the epidermis.Transdermal delivery includes injection or other delivery through anyportion of the skin or mucous membrane and absorption or permeationthrough the remaining portion. Absorption through intact skin can beenhanced by placing the active agent in an appropriate pharmaceuticallyacceptable vehicle before application to the skin. Passive topicaladministration may consist of applying the active agent directly to thetreatment site in combination with emollients or penetration enhancers.

A topically (e.g., transdermally) administrable pharmaceuticalformulation may also include an amount of a form of hyaluronic acidsufficient to transport the composition through the skin of a patientinto the epidermis or dermis where the composition remains untildischarged via the lymphatic system. Desirably, the active compound is1-5% by weight of the formulation and hyaluronic acid is 1-3% by weightof the formulation. Desirable forms of hyaluronic acid have a molecularweight greater than about 150,000 daltons and less than 750,000 daltons.Salts of hyaluronic acid are also desirable for use in the methodsencompassed by the present invention.

Many of the compounds of the present invention can be provided aspharmaceutically acceptable acid addition salts. Such pharmaceuticallyacceptable acid addition salts are those salts that retain thebiological effectiveness and properties of the free bases.

The sensitivity of the CCB analogs to hydrolysis by esterase enzymes canbe inferred by measuring their stability in human plasma. This measureprovides a qualitative in-vitro method of ranking the compounds in orderof relative stability and provides a useful comparison to CCBs withlonger half-lives (i.e. diltiazem, verapamil and nifedipine). Suchassays are available from commercial service providers such as MDSPharma Services. The assay is conducted in the following manner:

-   -   The test matrix is pooled human plasma;    -   The concentration of the analog being tested is 10 μM;    -   The mixture is incubated in duplicate at 37° C.;    -   The incubation is stopped at 0, 0.5, 1, 2 and 30 min by adding        an equal volume of acetonitrile; and    -   The extracted samples are analyzed by either (+)- or (−)-ESI        LC/MS using a pre-established generic method.    -   Data is expressed as % of the zero time samples.        General Synthetic Methodology

Compounds of the invention may be prepared as described herein. Inparticular, the method depicted in Scheme 1 may be used for thesynthesis of compounds having Formula I. The compounds may be preparedby heating a halogen substituted compound of general structure A with anamine of general structure B. The reaction may be conducted by heatingthe reactants together neat or in the presence of a solvent such asdichloromethane or tetrahydrofuran. A catalyst such as sodium iodide mayor may not be added.

The compounds of Formula I are further described as follows:

-   -   each a, b, c, d, e, f, and g is, independently, —CH₂—, —O—, —S—,        or a single bond;    -   each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₂₀ is,        independently: H, lower alkyl, lower alkyl substituted with        —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkyl substituted with fluorine or chlorine,        lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower        alkyl), lower alkoxyalkyl substituted with —CO₂(lower        alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or        chlorine, or CO₂R₁₀;    -   each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl;    -   R₁₈ is H, CN, or CO₂R₁₀; and    -   R₁₉ is CH₃ or H.        Starting Materials and Intermediate Compounds

The halogen substituted compounds of general structure A used to preparecompounds of Formula 1 exemplified in this invention are depicted inTable 1.

TABLE 1

1a

1b

1c

1d

1e

1f

1g

1h

1i

1j

1k

1l

1m

1n

1o

1p

1q

1r

1s

1t

1u The compounds of Table 1 may be alternatively described using thefollowing nomenclature: 1a: Dimethyl2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate; 1b: Methyl5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate; 1c: Ethyl5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate; 1d: Isopropyl5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate; 1e: Methyl5-chloro-2-(3,4-dimethoxyphenyl)-2-isopropylpentanoate; 1f:5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile; 1g: 1-Ethyl3-methyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate; 1h: Diethyl2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate; 1i: 1-tert-butyl3-methyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate; 1j:1-Isopropyl 3-methyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate;1k: Methyl 5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate; 1l: Ethyl5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate; 1m: Methyl5-bromo-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate; 1n: Methyl4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate; 1o: Ethyl5-bromo-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate; 1p: Isopropyl5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate; 1q: Methyl4-(5-bromo-2-cyano-1-methoxy-1-oxopentan-2-yl)benzoate; 1r: Methyl3-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate; 1s: Methyl3-(5-bromo-2-cyano-1-methoxy-1-oxopentan-2-yl)benzoate; 1t: Ethyl4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate; and 1u: Isopropyl4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate.

The amine compounds of general structure B used to prepare compounds ofFormula 1 exemplified in this invention are depicted in Table 2.

TABLE 2

2a

2b

2c

2d

2e

2f

2g

2h

2i

2j

2k

2l

2m

2n

2o The compounds of Table 2 may be alternatively described using thefollowing nomenclature: 2a: 2-(3,4-Dimethoxyphenyl)-N-methylethanamine;2b: Methyl 4-(2-(methylamino)ethyl)benzoate; 2c: Ethyl4-(2-(methylamino)ethyl)benzoate; 2d: Methyl3-(2-(methylamino)ethyl)benzoate; 2e: Ethyl3-(2-(methylamino)ethyl)benzoate; 2f: Isopropyl3-(2-(methylamino)ethyl)benzoate; 2g: Propyl3-(2-(methylamino)ethyl)benzoate; 2h: Methyl2-methoxy-5-(2-(methylamino)ethyl)benzoate; 2i: Dimethyl5-(2-(methylamino)ethyl)isophthalate; 2j: Methyl2-(4-(2-(methylamino)ethyl)phenoxy)acetate; 2k: Ethyl2-(4-(2-(methylamino)ethyl)phenoxy)acetate; 2l: Methyl2-(3-(2-(methylamino)ethyl)phenoxy)acetate; 2m: Butyl3-(2-(methylamino)ethyl)benzoate; 2n: 2-Methoxyethyl3-(2-(methylamino)ethyl)benzoate; and 2o: Methyl2-(3-(2-(methylamino)ethyl)phenyl)acetate;Compounds of Formula 1 Exemplified in this Invention

The compounds of Formula 1 exemplified in this invention are depicted inTable 3.

TABLE 3

3a

3b

3c

3d

3e

3f

3g

3h

3i

3j

3k

3l

3m

3n

3o

3p

3q

3r

3s

3t

3u

3v

3w

3x

3y

3z

3aa

3ab

3ac

3ad

3ae

3af

3ag

3ah

3ai

3aj

3ak

3al

3am

3an

3ao

3ap

3aq

3ar

3as

3at

3au The compounds of Table 3 may be alternatively described using thefollowing nomenclature: 3a: Dimethyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate;3b: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate;3c: Methyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate;3d: Ethyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate;3e: Isopropyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate;3f: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanoate;3g: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3h: Methyl4-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3i: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3j: 1-Ethyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate;3k: Diethyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate;3l: 1-tert-Butyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate;3m: 1-Isopropyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate;3n: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3o: Methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3p: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3q: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3r: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3s: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate;3t: Methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3u: Methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate;3v: Ethyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate;3w: Ethyl4-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3x: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate;3y: Methyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate;3z: Ethyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3aa: Ethyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate;3ab: Isopropyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate;3ac: Methyl4-(2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-1-methoxy-1-oxopentan-2-yl)benzoate;3ad: Methyl3-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate;3ae: Isopropyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3af: Propyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3ag: Methyl5-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)-2-methoxybenzoate;3ah: Methyl3-(2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-1-methoxy-1-oxopentan-2-yl)benzoate;3ai: Dimethyl5-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)isophthalate;3aj: Methyl3-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3ak: Methyl2-(4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate; 3al: Ethyl2-(4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate;3am: Methyl3-(3-cyano-6-((4-(methoxycarbonyl)phenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate;3an: Ethyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate;3ao: Isopropyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate;3ap: Methyl3-(2-((4-cyano-4-(3-(methoxycarbonyl)phenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3aq: Methyl2-(3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate;3ar: Butyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3as: 2-Methoxyethyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate;3at: Methyl2-(3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenyl)acetate;and 3au: Methyl2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate.

In order that this invention be more fully understood, the followingpreparative examples are set forth. These examples are for the purposeof illustration only and are not to be construed as limiting the scopeof the invention in any way.

EXAMPLES

Compounds needed as synthetic starting materials that were not availablefrom commercial sources were synthesized. If not mentioned otherwise,all evaporations were performed under reduced pressure, preferablybetween about 15 mm Hg and 100 mm Hg. The structure of final products,intermediates and starting materials was confirmed by standardanalytical methods such as elemental analysis, NMR and MS.

Preparation of starting materials and intermediate compounds used toprepare the compounds of Formula 1 exemplified in this invention aredescribed in the following examples.

For the Compounds Listed in Table 1 Example 15-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile (1f)

Method A Step 1:

To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrilein 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL(56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF).The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0mmol) of 2-bromopropane was added. The mixture was heated to reflux for2 hours (h) then left at 22° C. for about 16 h. A saturated aqueoussolution of NH₄Cl was added and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flashchromatography on silica gel eluting first with hexane and thengradually increasing to 15% ethyl acetate/hexane to give2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil.

Method A Step 2:

To a solution of 11.21 g (51.1 mmol) of2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 mL oftetrahydrofuran (THF) at −30° C., was slowly added 46.0 mL (46.0 mmol)of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixturewas stirred at −30° C. for 10 minutes and 9.40 mL (256 mmol) of1,3-dibromopropane was added dropwise. The mixture was warmed to 22° C.and stirred for about 16 h. A saturated aqueous solution of NH₄Cl wasthen added and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash chromatography on silica gel elutingfirst with hexane and then gradually increasing to 15% ethylacetate/hexane to give5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile as an oil.

Unless otherwise indicated, the following compounds were prepared byprocedures analogous to those described in Method A:

Example 2 1a: Dimethyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile, dimethyl carbonatewas substituted for 2-bromopropane and sodium hydride was substitutedfor NaHMDS. For Step 2, sodium hydride was substituted for NaHMDS.

Example 3 1b: Methyl 5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate

For Step 1, dimethyl carbonate was substituted for 2-bromopropane andsodium hydride was substituted for NaHMDS.

Example 4 1c: Ethyl 5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate

For Step 1, diethyl carbonate was substituted for 2-bromopropane andsodium hydride was substituted for NaHMDS.

Example 5 1d: Isopropyl5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate

For Step 1, isopropyl chloroformate was substituted for 2-bromopropane.

Example 6 1e: Methyl5-chloro-2-(3,4-dimethoxyphenyl)-2-isopropylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile, 2-iodopropane wassubstituted for 2-bromopropane and KHMDS was substituted for NaHMDS. ForStep 2,1-bromo-3-chloropropane was substituted for 1,3-dibromopropane.

Example 7 1g: 1-Ethyl 3-methyl2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile, ethyl chloroformatewas substituted for 2-bromopropane and lithium diisopropylamide (LDA)was substituted for NaHMDS. For Step 2, sodium hydride was substitutedfor NaHMDS.

Example 8 1h: Diethyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

For

Step 1, (3,4-dimethoxy-phenyl)-acetic acid ethyl ester was substitutedfor (3,4-Dimethoxyphenyl)acetonitrile, ethyl chloroformate wassubstituted for 2-bromopropane and lithium diisopropylamide (LDA) wassubstituted for NaHMDS. For Step 2, sodium hydride was substituted forNaHMDS.

Example 9 1i: 1-tert-butyl 3-methyl2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile, di-tert-butyldicarbonate was substituted for 2-bromopropane and LDA was substitutedfor NaHMDS. For Step 2, sodium hydride was substituted for NaHMDS.

Example 10 1j: 1-Isopropyl 3-methyl2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile, isopropylchloroformate was substituted for 2-bromopropane and LDA was substitutedfor NaHMDS. For Step 2, sodium hydride was substituted for NaHMDS.

Example 11 1k: Methyl 5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile and dimethyl sulfatewas substituted for 2-bromopropane.

Example 12 1l: Ethyl 5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid ethyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile and dimethyl sulfatewas substituted for 2-bromopropane.

Example 13 1m: Methyl 5-bromo-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile and diethyl sulfatewas substituted for 2-bromopropane.

Example 14 1n: Methyl 4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate

For Step 1, methyl 4-(cyanomethyl)benzoate was substituted for(3,4-Dimethoxyphenyl)acetonitrile. For Step 2, sodium hydride wassubstituted for NaHMDS.

Example 15 1o: Ethyl 5-bromo-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid ethyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile and diethyl sulfatewas substituted for 2-bromopropane.

Example 16 1p: Isopropyl5-bromo-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

For Step 1, (3,4-dimethoxy-phenyl)-acetic acid isopropyl ester wassubstituted for (3,4-Dimethoxyphenyl)acetonitrile and dimethyl sulfatewas substituted for 2-bromopropane.

Example 17 1q: Methyl4-(5-bromo-2-cyano-1-methoxy-1-oxopentan-2-yl)benzoate

For Step 1, methyl 4-(cyanomethyl)benzoate was substituted for(3,4-Dimethoxyphenyl)acetonitrile and dimethyl carbonate was substitutedfor 2-bromopropane. For Step 2, sodium hydride was substituted forNaHMDS.

Example 18 1r: Methyl 3-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate

For Step 1, methyl 3-(cyanomethyl)benzoate was substituted for(3,4-Dimethoxyphenyl)acetonitrile and sodium hydride was substituted forNaHMDS. For Step 2, sodium hydride was substituted for NaHMDS.

Example 19 1s: Methyl3-(5-bromo-2-cyano-1-methoxy-1-oxopentan-2-yl)benzoate

For Step 1, methyl 3-(cyanomethyl)benzoate was substituted for(3,4-Dimethoxyphenyl)acetonitrile and dimethyl carbonate was substitutedfor 2-bromopropane.

Example 20 1t: Ethyl 4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate

Ethyl 4-(1-cyano-2-methylpropyl)benzoate was obtained by NaOH hydrolysisof methyl 4-(1-cyano-2-methylpropyl)benzoate (obtained as anintermediate in the transformations described in Example 14) andsubsequent esterification by heating in ethanol and catalytic H₂SO₄. Theethyl ester was then subjected to the procedure of Method A, Step 2.

Example 21 1u: Isopropyl 4-(6-bromo-3-cyano-2-methylhexan-3-yl)benzoate

Isopropyl 4-(1-cyano-2-methylpropyl)benzoate was obtained by NaOHhydrolysis of methyl 4-(1-cyano-2-methylpropyl)benzoate (obtained as anintermediate in the transformations described in Example 14) andsubsequent esterification by heating in 2-propanol and catalytic H₂SO₄.The isopropyl ester was then subjected to the procedure of Method A,Step 2.

For the Compounds Listed in Table 2 Example 22 Methyl4-(2-(methylamino)ethyl)benzoate (2b)

To a solution of 2.02 g (10.0 mmol) of 4-(2-aminoethyl)benzoic acidhydrochloride in 25 mL of methanol was added 1.5 mL of H₂SO₄. Themixture was heated to reflux and became a homogeneous solution after 1h. The solution was refluxed for about 16 h, cooled to 22° C. andconcentrated to about 10 mL by evaporation. The solution was dilutedwith 100 mL of water, made basic with 1 N NaOH and extracted with 100 mLof dichloromethane (DCM). The aqueous layer was back-extracted with DCM(4×100 mL). The combined extracts were dried (Na₂SO₄) and evaporated togive methyl 4-(2-aminoethyl)benzoate as a colorless oil. The materialwas used directly in the subsequent transformation.

To a solution of methyl 4-(2-aminoethyl)benzoate in 30 mL of DCM at 0°C. was added 1.10 mL (6.31 mmol) of diisopropylethylamine (DIEA)followed by 0.850 mL (6.11 mmol) of trifluoroacetic anhydride. Thereaction was allowed to warm to 22° C. and stirred for 2 h. The reactionwas washed with 30 mL of saturated NaHCO₃. The aqueous solution wasback-extracted with 30 mL of DCM and the combined organic extracts weredried (Na₂SO₄) and evaporated to give methyl4-(2-(2,2,2-trifluoroacetamido)ethyl)benzoate as a solid. The materialwas further purified by flash chromatography on silica gel, elutingfirst with hexane and then gradually increasing to 20% ethylacetate/hexane.

To a solution of 1.53 g (5.54 mmol) of methyl4-(2-(2,2,2-trifluoroacetamido)ethyl)benzoate in 30 mL ofdimethylformamide (DMF) at 0° C. was added 1.91 g (13.9 mmol) ofpotassium carbonate and 1.75 mL (27.7 mmol) of iodomethane. The reactionwas warmed to 22° C. and left to stir for about 16 h. A whiteprecipitate resulted which was collected. The solid was washed well with100 mL of water to dissolve the potassium salts, collected and washedagain with 50 mL of hexane. The resulting crude methyl4-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate was used directlyin the next step.

A solution of 0.80 g (5.5 mmol) of sodium hydride (60% mineral oildispersion) dissolved in 20 mL of methanol was prepared and added to aseparate solution of 1.05 g (3.64 mmol) of methyl4-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate dissolved in 12mL of THF at 0° C. The solution was warmed to 22° C. and stirred forabout 36 h. Water was added (100 mL) and the solution was acidified topH 1 with 1 N HCl. The mixture was washed with DCM (2×100 mL) and thenbasified with 1 N NaOH to pH 8-9. The aqueous solution was extractedwith DCM (3×100 mL) and the organic extracts dried (Na₂SO₄) andevaporated to give 2b as a white solid which was used without furtherpurification in the subsequent transformation.

Example 23 2c: Ethyl 4-(2-(methylamino)ethyl)benzoate

To a solution of 2.72 g (13.5 mmol) of 4-(2-aminoethyl)benzoic acidhydrochloride in 67.5 mL of 1 N NaOH and 30 mL of dioxane was added 3.24g (14.9 mmol) of di-tert-butyl dicarbonate (BOC₂O) in 10 mL of dioxaneat 22° C. The solution was stirred for 2 h at 22° C. and an additional1.66 g (7.61 mmol) of BOC₂O was added. After stirring another 30 min thereaction was poured into 250 mL of ice water and the mixture acidifiedwith 1 N HCl to about pH 2, extracted with 250 mL of ethyl acetate,dried (Na₂SO₄) and evaporated to give a white solid. The solid wasrecrystallized from 50 mL of ethyl acetate to remove the excess BOC₂Oand to yield 4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid as awhite solid.

To a solution of 1.96 g (7.39 mmol) of4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid in 25 mL of DMF wasadded 4.43 g (32.1 mmol) of potassium carbonate and 3.00 mL (37.2 mmol)of iodoethane at 0° C. The mixture was warmed to 22° C. and stirred forabout 16 h. The reaction was then diluted with 20 mL of water and 100 mLof saturated NaHCO₃. The mixture was extracted with DCM (3×200 mL) andthe combined organics were washed with 100 mL of water, dried (MgSO₄)and evaporated to give ethyl4-(2-(tert-butoxycarbonylamino)ethyl)benzoate as a sticky off-whitesolid.

Method B Step 1:

To a solution of 1.25 g (4.26 mmol) of ethyl4-(2-(tert-butoxycarbonylamino)ethyl)benzoate in 40 mL of dry THF undera nitrogen atmosphere was added dropwise, 4.7 mL (4.7 mmol) of NaHMDS(1.0 M in THF) at 0° C. After stirring for 10 min, 0.50 mL (5.3 mmol) ofdimethyl sulfate was added and the reaction was warmed to 22° C. andstirred for about 16 h. The reaction was quenched by adding 25 mL ofsaturated NaHCO₃ and the mixture was extracted with DCM (2×25 mL). Thecombined organic extracts were dried (Na₂SO₄) and evaporated and theresidue was purified by flash chromatography on silica gel, elutingfirst with hexane and then gradually increasing to 10% ethylacetate/hexane to give ethyl4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate as a colorlessoil.

Method B Step 2:

To a solution of 0.907 g (2.95 mmol) of ethyl4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in 10 mL of DCM at0° C. was added 2.0 mL (26 mmol) of trifluoroacetic acid (TFA). Thereaction was warmed to 22° C., stirred for 3 h and the solvents werethen evaporated. The residue was partitioned between 100 mL of ethylacetate and 100 mL of 1 N NaOH which had been saturated with NaCl. Theaqueous layer was back-extracted with ethyl acetate (6×50 mL) and thecombined organics were dried (Na₂SO₄) and evaporated to give 2c as acolorless oil.

Example 24 2d: Methyl 3-(2-(methylamino)ethyl)benzoate

To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. Themixture was refluxed for about 16 h, cooled to 22° C. and filtered. Thefiltrate was evaporated and the residue was purified by flashchromatography on silica gel, eluting first with hexane and thengradually increasing to 15% ethyl acetate/hexane to give methyl3-(cyanomethyl)benzoate.

To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) ofsodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroaceticacid. The mixture was warmed to 22° C. and stirred for about 16 h. About100 mL of water was carefully added to the mixture (gas evolution). Themixture was extracted with ethyl acetate (5×50 mL). The organic phasewas washed with brine, dried (Na₂SO₄), filtered and evaporated to givemethyl 3-(2-aminoethyl)benzoate which was used in the next step withoutpurification.

Method C:

To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mLtetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC₂O. The mixturewas stirred for about 16 h at 22° C. and 100 mL of water was added. Themixture was extracted with ethyl acetate (2×100 mL) and the organicphase was washed with brine, dried (Na₂SO₄) and evaporated. The residuewas purified by flash chromatography on silica gel, eluting first withhexane and then gradually increasing to 20% ethyl acetate/hexane to givemethyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was furtherconverted to 2d in a manner analogous to Method B.

Example 25 2e: Ethyl 3-(2-(methylamino)ethyl)benzoate

To a solution of 1.90 g (10.6 mmol) of methyl 3-(2-aminoethyl)benzoatein 106 mL of 1 N NaOH and 50 mL of dioxane was added 3.47 g (15.9 mmol)of BOC₂O in 10 mL of dioxane at 22° C. The solution was stirred for 2 hat 22° C. and then acidified to pH 2 by addition of 1 N HCl. Theaqueous/organic mixture was saturated by stirring with solid NaCl andthen extracted with DCM (5×100 mL). The combined organic extracts weredried (Na₂SO₄) and evaporated to give3-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid as a foamy white solidwhich was used subsequently without purification.

Transformation of 3-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid toethyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate with iodoethane andpotassium carbonate was accomplished in a manner analogous to thatdescribed in Example 23.

Transformation of ethyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate to2e was accomplished in a manner analogous to that described in Method B.

Example 26 2f: Isopropyl 3-(2-(methylamino)ethyl)benzoate

Transformation of 3-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid toisopropyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate was accomplishedwith 2-iodopropane and potassium carbonate in a manner analogous to thatdescribed in Example 23.

Transformation of isopropyl3-(2-(tert-butoxycarbonylamino)ethyl)benzoate to 2f was accomplished ina manner analogous to that described in Method B.

Example 27 2g: Propyl 3-(2-(methylamino)ethyl)benzoate

To a solution of 0.580 g (1.98 mmol) of methyl3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in 5 mL of dioxanewas added 10 mL of 1 N NaOH. The mixture was stirred at 22° C. for 2 hand then acidified to ca. pH 1 with 1 N HCl. The mixture was thenextracted with DCM (4×25 mL), dried (Na₂SO₄) and evaporated to give3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoic acid as a foamywhite solid which was subsequently used without purification.

Transformation of 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoicacid to propyl 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate wasaccomplished with 1-iodopropane and potassium carbonate in a manneranalogous to that described in Example 23.

Transformation of propyl3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate to 2g wasaccomplished in a manner analogous to that described in Method B Step 2.

Example 28 2h: Methyl 2-methoxy-5-(2-(methylamino)ethyl)benzoate

To a solution of 1.01 g (6.09 mmol) of 5-formyl-2-hydroxybenzoic acid in25 mL of acetone was added 4.25 g (30.5 mmol) of potassium carbonate and1.15 mL (18.3 mmol) of iodomethane. The mixture was heated to reflux forabout 16 h, cooled to 22° C. and filtered. The collected solid waswashed with acetone. The filtrates were combined, evaporated and theresidue purified by flash chromatography on silica gel eluting with amixture of hexane and ethyl acetate to give methyl5-formyl-2-methoxybenzoate as an off-white solid.

To a solution of 0.609 g (3.66 mmol) of 5-formyl-2-methoxybenzoate in 10mL of acetic acid at 22° C. was added 2.2 mL (22 mmol) of n-butylaminefollowed by 0.337 mL (5.50 mmol) of nitromethane. The mixture was heatedto reflux for 3 h, cooled to 22° C. and poured into 250 mL of water. Ayellow precipitate resulted which dissolved when the mixture wasextracted with 200 mL of ethyl acetate. The organic layer was washedwith saturated NaHCO₃ (2×100 mL), dried (Na₂SO₄) and evaporated. Theresidue was purified by flash chromatography on silica gel eluting witha mixture of hexane and ethyl acetate to give methyl2-methoxy-5-(2-nitrovinyl)benzoate.

To a solution of 0.429 g (1.81 mmol) of2-methoxy-5-(2-nitrovinyl)benzoate in 18 mL of methanol was added 0.75mL of 12 N HCl followed by 50 mg of 10% palladium on carbon. The mixturewas stirred for 3 h under a balloon hydrogen atmosphere then degassedwith nitrogen and filtered. Evaporation gave methyl5-(2-aminoethyl)-2-methoxybenzoate hydrochloride as a sticky oil.

Transformation of methyl 5-(2-aminoethyl)-2-methoxybenzoate to 2h wasaccomplished in a manner analogous to that described in Method C andMethod B.

Example 29 2i: Dimethyl 5-(2-(methylamino)ethyl)isophthalate

To a solution of 3.15 g (14.1 mmol) of dimethyl5-(hydroxymethyl)isophthalate (prepared as described in Dimick et al.,J. Am. Chem. Soc. (1999) 121, No. 44, 10286-10296) in 60 mL of DCM wasadded 7.34 g (84.4 mmol) of MnO₂. The mixture was stirred at reflux forabout 16 h and an additional 3.5 g of MnO₂ was added. Refluxing wascontinued for another 6 h and the mixture was cooled, filtered throughcelite and evaporated to give dimethyl 5-formylisophthalate as a whitesolid which was used subsequently without purification.

To a solution of 2.45 g (11.0 mmol) of dimethyl 5-formylisophthalate in30 mL of methanol was added 1.48 mL (27.6 mmol) of nitromethane and 1.53mL (11.0 mmol) of triethylamine (TEA). The solution was stirred at 22°C. for about 16 h, evaporated then coevaporated with xylenes. Theresidue was purified by flash chromatography on silica gel, elutingfirst with 5% ethyl acetate/hexane and then gradually increasing to 20%ethyl acetate/hexane which gave dimethyl5-(1-hydroxy-2-nitroethyl)isophthalate as a solid.

To a solution of 2.29 g (8.09 mmol) of dimethyl5-(1-hydroxy-2-nitroethyl)isophthalate in 50 mL of DCM and 10 mL ofacetic anhydride at 22° C. was added 100 mg of 4-dimethylaminopyridine.The solution was stirred at 22° C. for 1.5 h, evaporated and thencoevaporated with xylenes (the material darkened slightly). The residuewas partitioned between 100 mL of DCM and 50 mL of 1 N HCl. The organiclayer was washed with water (50 mL), satd NaHCO₃, dried (Na₂SO₄) andevaporated. The resulting residue was purified by flash chromatographyon silica gel eluting with DCM to give dimethyl5-(2-nitrovinyl)isophthalate as a light yellow solid.

To a solution of 365 mg (1.38 mmol) of dimethyl5-(2-nitrovinyl)isophthalate in 15 mL of methanol and 0.46 mL of 12 NHCl, was added 80 mg of 10% palladium on carbon. The mixture was stirredunder a hydrogen balloon atmosphere for 7 h then filtered through celiteand evaporated to give dimethyl 5-(2-aminoethyl)isophthalatehydrochloride as a white solid which was used as such immediately in thenext step.

Transformation of dimethyl 5-(2-aminoethyl)isophthalate hydrochloride to2i was accomplished in a manner analogous to Method C (using DMF insteadof THF and adding TEA) followed by Method B.

Example 30 2j: Methyl 2-(4-(2-(methylamino)ethyl)phenoxy)acetate

Method D:

To a solution of 1.00 g (5.75 mmol) of 4-(2-aminoethyl)phenol in 5 mL ofdioxane at 22° C. was added 2 mL of 1 N NaOH followed by 1.88 g (8.62mmol) of BOC₂O dissolved in 2 mL of dioxane. The mixture was stirred at22° C. for 2 h and then neutralized by adding 25 mL of saturated NaHCO₃which resulted in a pH of about 7.5-8. The aqueous layer was separatedand extracted with DCM (3×50 mL). The organics were combined, dried(Na₂SO₄) and evaporated. The residue was purified by flashchromatography on silica gel eluting with a mixture of hexane and ethylacetate to give tert-butyl 4-hydroxyphenethylcarbamate as a colorlessoil.

Method E:

To a solution of 1.11 g (4.70 mmol) of tert-butyl4-hydroxyphenethylcarbamate in 20 mL of DMF at 22° C. was added 1.3 g(9.4 mmol) of potassium carbonate and 0.700 mL (5.87 mmol) of benzylbromide. The mixture was stirred for about 16 h at 22° C., diluted with100 mL of water and extracted with ethyl acetate (3×75 mL). The organiclayers were combined, washed with 100 mL of 1 N HCl, dried (Na₂SO₄), andevaporated. The residue was purified by flash chromatography on silicagel eluting with a mixture of hexane and ethyl acetate to givetert-butyl 4-(benzyloxy)phenethylcarbamate as an oil which latersolidified under vacuum. Transformation of tert-butyl4-(benzyloxy)phenethylcarbamate to tert-butyl4-(benzyloxy)phenethyl(methyl)carbamate was accomplished in a manneranalogous to Method B Step 1.

To a solution of 1.13 g (3.32 mmol) of tert-butyl4-(benzyloxy)phenethyl(methyl)carbamate in 15 mL of methanol was added35 mg of 10% palladium on carbon. The reaction was stirred under ahydrogen balloon atmosphere for 6 h, filtered through celite andevaporated to give tert-butyl 4-hydroxyphenethyl(methyl)carbamate as acolorless oil which was subsequently used without purification.

Transformation of tert-butyl 4-hydroxyphenethyl(methyl)carbamate to 2jwas accomplished in a manner analogous to Method E (using methyl2-bromoacetate instead of benzyl bromide and acetone in place of DMF)followed by Method B Step 2.

Example 31 2k: Ethyl 2-(4-(2-(methylamino)ethyl)phenoxy)acetate

Transformation of tert-butyl 4-hydroxyphenethyl(methyl)carbamate to 2kwas accomplished in a manner analogous to Method E (using ethyl2-bromoacetate instead of benzyl bromide and acetone in place of DMF)followed by Method B Step 2.

Example 32 2l: Methyl 2-(3-(2-(methylamino)ethyl)phenoxy)acetate

Transformation of 2-(3-methoxyphenyl)ethanamine to tert-butyl3-methoxyphenethyl(methyl)carbamate was accomplished in a manneranalogous to Method D followed by Method B Step 1.

A solution of 3.16 g (11.9 mmol) of tert-butyl3-methoxyphenethyl(methyl)carbamate in 10 mL of 48% aqueous HBr wasprepared and heated to 110° C. for about 16 h. The solution was cooledto 0° C. and carefully neutralized to slightly basic pH with 10 N NaOH.To the cooled mixture was added 3.90 g (17.8 mmol) of BOC₂O in 10 mL ofdioxane. The reaction was warmed to 22° C., stirred for 2 h and 1 N HClwas added carefully to adjust to about pH 7. The mixture was partitionedbetween 100 mL of saturated NaHCO₃ and ethyl acetate. The organic layerwas dried (Na₂SO₄) and evaporated. The residue was purified by flashchromatography on silica gel eluting with a mixture of hexane and ethylacetate to give tert-butyl 3-hydroxyphenethyl(methyl)carbamate.

Transformation of tert-butyl 3-hydroxyphenethyl(methyl)carbamate to 21was accomplished in a manner analogous to Method E (using methyl2-bromoacetate instead of benzyl bromide and acetone in place of DMF)followed by Method B Step 2.

Example 33 2m: Butyl 3-(2-(methylamino)ethyl)benzoate

Transformation of 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoicacid to butyl 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate wasaccomplished with 1-iodobutane and potassium carbonate in a manneranalogous to that described in Example 23. Transformation of butyl3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate to 2m wasaccomplished in a manner analogous to that described in Method B Step 2.

Example 34 2n: 2-Methoxyethyl 3-(2-(methylamino)ethyl)benzoate

Transformation of 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoicacid to 2-methoxyethyl3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate was accomplishedwith 1-bromo-2-methoxyethane and potassium carbonate in a manneranalogous to that described in Example 23.

Transformation of 2-methoxyethyl3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate to 2n wasaccomplished in a manner analogous to that described in Method B Step 2.

Example 35 2o: Methyl 2-(3-(2-(methylamino)ethyl)phenyl)acetate

Conversion of 2-(3-bromophenyl)ethanamine to tert-butyl3-bromophenethyl(methyl)carbamate was accomplished in a manner analogousto Method C followed by Method B, Step 1.

To a solution of 200 mg (1.51 mmol) of dimethylmalonate in 4 mL ofdioxane at 22° C. was added 61.0 mg (1.53 mmol) of sodium hydride (60%dispersion in mineral oil). After the mixture was stirred for 10minutes, 61 μL (0.06 mmol) of tri-tert-butylphosphine (1 M in toluene),17.4 mg (0.030 mmol) of bis(dibenzylideneacetone)palladium(0) and 333 mg(1.06 mmol) of tert-butyl 3-bromophenethyl(methyl)carbamate were addedsequentially and the mixture heated to reflux for about 16 h undernitrogen. After cooling to 22° C., the solvent was evaporated and theresidue partitioned between saturated NH₄Cl and ethyl acetate. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andevaporated to give dimethyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)malonate whichwas used directly in the next step without further purification.

To 429 μL (10.6 mmol) of methanol was slowly added 85 mg (2.1 mmol) ofsodium hydride (60% dispersion in mineral oil). This mixture was thenadded to a separate solution of 387 mg (1.06 mmol) of dimethyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)malonate in 5 mLof tetrahydrofuran. The resulting solution was refluxed for 2 h thencooled to 22° C. An additional 85 mg of NaH in 429 ml of methanol wasadded and the solution was again heated to reflux for about 16 h. Thesolvent was evaporated and the residue partitioned between saturatedNH₄Cl and ethyl acetate. The organic layer was washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashchromatography on silica gel, eluting first with hexane and thengradually increasing to 15% ethyl acetate/hexane to give methyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)acetate.

Conversion of methyl2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)acetate to 2o wasaccomplished in a manner analogous to Method B, Step 2.

Preparation of Compounds of Formula 1 Exemplified in this Invention:

Preparation of compounds of Formula 1 exemplified in this invention wasaccomplished by the general procedure of Method F. The conditions ofMethod F are suitable for the synthesis of the compounds described inthe below Examples. In some cases, the reaction was conducted withoutevaporation of THF or other suitable non-reactive organic solvents wereused instead. In some cases a few crystals of sodium iodide were addedto help accelerate the reaction or a base such as DIEA was added. Thesevariations did not significantly alter the outcome of the generalprocedure.

Example 36 Ethyl4-(2-44-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate(3r)

Method F:

A solution of 0.326 g (0.961 mmol) of 1f in 1 mL of THF and a separatesolution of 0.292 g (1.41 mmol) of 2c in 1 mL of THF were combined. Theresulting solution was heated in a 90° C. oil bath and the THF wasevaporated under a slow stream of nitrogen. The resulting mixture wasstirred under nitrogen at 85° C. for 18 h, cooled to 22° C. andpartitioned between saturated NaHCO₃ and ethyl acetate. The organiclayer was dried (Na₂SO₄) and evaporated and the residue purified byflash chromatography on silica gel, eluting first with DCM and thengradually increasing to 2% methanol/DCM to give 3r as a colorless oil;MS found M+H=467. The oxalate salt of 3r was recrystallized from ethylacetate; mp 111-112° C.

Unless otherwise indicated, the following Examples were prepared byprocedures analogous to Method F:

Example 37 3a: Dimethyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate

Reaction of 1a with 2a produced 3a. MS found M+H=504. The oxalate saltof 3a was recrystallized from ethyl acetate; mp 165-166° C.

Example 38 3b: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate

To a solution of 0.349 g (0.694 mmol) of 3a in 20 mL of THF at 22° C.was added 0.281 mL (6.94 mmol) of methanol followed by 56 mg (1.39 mmol)of NaH (60% dispersion in mineral oil). The reaction was refluxed for 1h, cooled to 22° C. and diluted with 100 mL of DCM. The mixture waswashed with 50 mL of saturated NaHCO₃, 50 mL of water, dried, andevaporated to give an oil. The oil was purified by flash chromatographyon silica gel, eluting first with 2% methanol/DCM and then graduallyincreasing to 4% methanol/DCM to give 3b as a colorless oil; MS foundM+H=446. The oxalate salt of 3r was recrystallized from ethyl acetate;mp 112-113.5° C.

Example 39 3c: Methyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate

Reaction of 1b with 2a produced 3c. MS found M+H=471. The oxalate saltof 3c was recrystallized from ethyl acetate; mp 129-130° C.

Example 40 3d: Ethyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate

Reaction of 1c with 2a produced 3d. MS found M+H=485. The oxalate saltof 3d was recrystallized from ethyl acetate; mp 77-78° C.

Example 41 3e: Isopropyl2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)pentanoate

Reaction of 1d with 2a produced 3e. MS found M+H=499. The oxalate saltof 3e was recrystallized from ethyl acetate; mp 66-67° C.

Example 42 3f: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanoate

Reaction of 1e with 2a produced 3f. MS found M+H=488. The oxalate saltof 3f was recrystallized from ethyl acetate; mp 158-159° C.

Example 43 3g: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2b produced 3g. MS found M+H=453. The oxalate saltof 3g was recrystallized from ethyl acetate; mp 130-131° C.

Example 44 3h: Methyl4-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1e with 2b produced 3h. MS found M+H=486. The oxalate saltof 3h was recrystallized from ethyl acetate; mp 129-131° C.

Example 45 3i: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1b with 2b produced 3i. MS found M+H=469. The oxalate saltof 3i was recrystallized from ethyl acetate; mp 80-83° C.

Example 46 3j: 1-Ethyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate

Reaction of 1g with 2a produced 3j. MS found M+H=518. The oxalate saltof 3j was recrystallized from isopropanol/ether; mp 146-149° C.

Example 47 3k: Diethyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate

Reaction of 1h with 2a produced 3k. MS found M+H=532. The oxalate saltof 3k was recrystallized from ethyl acetate/ether; mp 101-104° C.

Example 48 3l: 1-tert-Butyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate

Reaction of 1i with 2a produced 31. MS found M+H=546. The oxalate saltof 31 was recrystallized from ethyl acetate/hexane; mp 161-163° C.

Example 49 3m: 1-Isopropyl 3-methyl2-(3-((3,4-dimethoxyphenethyl)(methyl)amino)propyl)-2-(3,4-dimethoxyphenyl)malonate

Reaction of 1j with 2a produced 3m. MS found M+H=532. The oxalate saltof 3m was recrystallized from methanol/ether; mp 157-159° C.

Example 50 3n: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1b with 2c produced 3n. MS found M+H=483. The oxalate saltof 3n was recrystallized from ethyl acetate; mp 88-89° C.

Example 51 3o: Methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2d produced 3o. MS found M+H=453. The oxalate saltof 3o was recrystallized from ethyl acetate; mp 135-136° C.

Example 52 3p: Methyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1c with 2b produced 3p. MS found M+H=483. The oxalate saltof 3p was recrystallized from ethyl acetate; mp 75-77° C.

Example 53 3q: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1c with 2c produced 3q. MS found M+H=497. The oxalate saltof 3q was recrystallized from ethyl acetate; mp 83-84° C.

Example 54 3r: Ethyl4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2c produced 3r. MS found M+H=467. The oxalate saltof 3r was recrystallized from ethyl acetate; mp 111-112° C.

Example 55 3s: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

Reaction of 1k with 2a produced 3s. MS found M+H=460. The oxalate saltof 3s was recrystallized from ethyl acetate; mp 88-89° C.

Example 56 3t: Methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1b with 2d produced 3t. MS found M+H=469. The oxalate saltof 3t was recrystallized from ethyl acetate; mp 94-95° C.

Example 57 3u: Methyl 3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-ethoxy-5-oxopentyl)(methyl)amino)ethyl)benzoate

Reaction of 1c with 2d produced 3u. MS found M+H=483. The oxalate saltof 3u was recrystallized from ethyl acetate; mp 89-91° C.

Example 58 3v: Ethyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

Reaction of 1l with 2a produced 3v. MS found M+H=474. The oxalate saltof 3v was recrystallized from ethyl acetate; mp 118-121° C.

Example 59 3w: Ethyl4-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1e with 2c produced 3w. MS found M+H=500. The oxalate saltof 3w was recrystallized from ethyl acetate; mp 121-123° C.

Example 60 3x: Methyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate

Reaction of 1m with 2a produced 3x. MS found M+H=474. The oxalate saltof 3x was recrystallized from methanol/ethyl acetate; mp 148-150° C.

Example 61 3y: Methyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate

Reaction of 1n with 2a produced 3y. MS found M+H=453. The oxalate saltof 3y was recrystallized from methanol/ether; mp 179-182° C.

Example 62 3z: Ethyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2e produced 3z. MS found M+H=467. The oxalate saltof 3z was recrystallized from ethyl acetate; mp 128-129° C.

Example 63 3aa: Ethyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-ethylpentanoate

Reaction of 1o with 2a produced 3aa. MS found M+H=488. The oxalate saltof 3aa was recrystallized from methanol/ethyl acetate; mp 122-124° C.

Example 64 3ab: Isopropyl5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-methylpentanoate

Reaction of 1p with 2a produced 3ab. MS found M+H=488. The oxalate saltof 3ab was recrystallized from methanol/ethyl acetate; mp 85-87° C.

Example 65 3ac: Methyl4-(2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-1-methoxy-1-oxopentan-2-yl)benzoate

Reaction of 1q with 2a produced 3ac. MS found M+H=469. The oxalate saltof 3ac was recrystallized from methanol/ether; mp 133-136° C.

Example 66 3ad: Methyl3-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate

Reaction of 1r with 2a produced 3ad. MS found M+H=453. The oxalate saltof 3ad was recrystallized from methanol/ether; mp 158-159° C.

Example 67 3ae: Isopropyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2f produced 3ae. MS found M+H=481. The oxalate saltof 3ae was recrystallized from ethyl acetate; mp 130-132° C.

Example 68 3af: Propyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2g produced 3af. MS found M+H=481. The oxalate saltof 3af was recrystallized from ethyl acetate; mp 110-114° C.

Example 69 3ag: Methyl5-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)-2-methoxybenzoate

Reaction of 1f with 2h produced 3ag. MS found M+H=483. The oxalate saltof 3ag was recrystallized from ethyl acetate; mp 76-81° C.

Example 70 3ah: Methyl3-(2-cyano-5-((3,4-dimethoxyphenethyl)(methyl)amino)-1-methoxy-1-oxopentan-2-yl)benzoate

Reaction of is with 2a produced 3ah. MS found M+H=469. The oxalate saltof 3ah was recrystallized from methanol/ether; mp 132-139° C.

Example 71 3ai: Dimethyl5-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)isophthalate

Reaction of 1f with 2i produced 3ai. MS found M+H=511. The oxalate saltof 3ai was recrystallized from hexane/ethyl acetate; mp 100-103° C.

Example 72 3aj: Methyl3-(2-((4-(3,4-dimethoxyphenyl)-4-(methoxycarbonyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1e with 2d produced 3aj. MS found M+H=486. The oxalate saltof 3aj was recrystallized from ethyl acetate; mp 87-90° C.

Example 73 3ak: Methyl2-(4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate

Reaction of 1f with 2j produced 3ak. MS found M+H=483. The oxalate saltof 3ak was recrystallized from ethyl acetate.

Example 74 3al: Ethyl2-(4-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate

Reaction of 1f with 2k produced 3al. MS found M+H=497. The oxalate saltof 3al was recrystallized from ethyl acetate.

Example 75 3am: Methyl3-(3-cyano-6-((4-(methoxycarbonyl)phenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate

Reaction of 1r with 2b produced 3am. MS found M+H=451. The oxalate saltof 3am was recrystallized from methanol/ether; mp 108-112° C.

Example 76 3an: Ethyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate

Reaction of 1t with 2a produced 3an. MS found

M+H=467. The oxalate salt of 3an was recrystallized from methanol/ether;mp 159-163° C.

Example 77 3ao: Isopropyl4-(3-cyano-6-((3,4-dimethoxyphenethyl)(methyl)amino)-2-methylhexan-3-yl)benzoate

Reaction of 1u with 2a produced 3ao. MS found M+H=481. The oxalate saltof 3ao was recrystallized from methanol/ether; mp 165-167° C.

Example 78 3ap: Methyl3-(2-((4-cyano-4-(3-(methoxycarbonyl)phenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1r with 2d produced 3ap. MS found M+H=451. The oxalate saltof 3ap was recrystallized from methanol/ether; mp 129-136° C.

Example 79 3aq: Methyl2-(3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenoxy)acetate

Reaction of 1f with 21 produced 3aq. MS found M+H=483. The oxalate saltof 3aq was recrystallized from methanol/ether; mp 96-100° C.

Example 80 3ar: Butyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2m produced 3ar. MS found M+H=495. The oxalate saltof 3ar was recrystallized from methanol/ether; mp 97-103° C.

Example 81 3as: 2-Methoxyethyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with 2n produced 3as. MS found M+H=497. The oxalate saltof 3ar was recrystallized from methanol/ether.

Example 82 3at: Methyl2-(3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)phenyl)acetate

Reaction of 1f with 2o produced 3at. MS found M+H=467. The oxalate saltof 3at was recrystallized from ethyl acetate; mp 77-82° C.

Example 83 3au: Methyl2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Reaction of 1f with N-methyl-2-phenylethanamine produced2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrilewhich was further reacted in a manner analogous to the procedurereported in Liang, C. D. et al., Tetrahedron Lett., (1986) 27,1971-1974.

To 331 mg (0.839 mmol) of2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrilein 8.3 mL of benzene was added 226 mg (1.01 mmol) ofpalladium(II)acetate and the mixture was stirred for 72 h at 22° C.under nitrogen. The solution was transferred into a pressure flask, 10mL of methanol was added and the mixture was treated with carbonmonoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) oftriethylamine, the mixture was filtered through a pad of celite andevaporated to give a crude mixture of 3au and2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile.In order to afford purification, a solution of 57 mg of the crudeproduct was dissolved in 1 mL of methanol and treated with 63 μL of 10 NNaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOHand 2 mL of methanol was added. The solution was heated to 50° C. thencooled to 22° C., evaporated and partitioned between ether and 0.5 NNaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl thenextracted with ethyl acetate (3x). The combined organic layers weredried (Na₂SO₄) and evaporated to give2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoicacid. The carboxylic acid was esterified by treating with 44 mg (0.24mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followedby addition of 8 mL of methanol and continued stirring for about 16hours at 22° C. The solvent was evaporated and the residue was purifiedby flash chromatography on silica gel, eluting first withdichloromethane and then gradually increasing to 3%methanol/dichloromethane to give 3au. MS found M+H=453. Substitution ofthe ester group in the indicated ortho-position of the phenyl ring wasconfirmed by ¹H NMR analysis.

Example 84 Calcium Channel Binding Data

Calcium channel binding inhibition constants (IQ were determined asfollows.

Whole brain membranes of male Wistar derived rats weighing 175±25 g wereprepared in HEPES buffer pH 7.4. A 10 mg aliquot was incubated with, forexample, 0.4 nM [³H](−)-Desmethoxyverapamil (D-888)(Amersham, TRK-834)for 60 minutes at 25° C. Non-specific binding was estimated in thepresence of 10 μM D-600(Sigma, M-115). Membranes were filtered andwashed, the filters are then counted to determine[³H](−)-Desmethoxyverapamil (D-888) specifically bound. Alldeterminations were performed in duplicate. Specific binding wasdetermined as the difference of total and nonspecific binding. The K_(i)values were calculated using the equation of Cheng and Prusoff (Cheng,Y. et al. Biochem. Pharmacol. (1973) 22, 3099-3018) using the observedIC₅₀ of the tested compound, the concentration of the radioligandemployed in the assay, and the historical values for the K_(d) of theligand (obtained experimentally at MDS Pharma Services).

The same method was used to determine the K_(i) for the compounds listedin Table 4.

TABLE 4 K_(i) (μM) Compound # Structure Ca Channel 3a-oxalate

++ 3b-oxalate

−− verapamil- oxalate

++++ verapamil-HCl

++++ 3c-oxalate

+++ 3d-oxalate

+++ 3e-oxalate

+++ 3f-oxalate

+++ 3g-oxalate

+++ 3h-oxalate

+++ 3i-oxalate

++ 3j-oxalate

++ 3k-oxalate

+ 3l-oxalate

+++ 3m-TFA

+++ 3m-oxalate

+++ 3n-oxalate

+++ 3o-oxalate*

++++ 3p-oxalate

+++ 3q-oxalate

+++ 3r-oxalate

++++ 3s-oxalate

+ 3t-oxalate

+++ 3u-oxalate

++++ 3v-oxalate

++ 3w-oxalate

+++ 3x-oxalate

+ 3y-oxalate

+++ 3z-oxalate

++++ 3aa-oxalate

+++ 3ab-oxalate

++ 3ac-oxalate

++ 3ad-oxalate

++++ 3ae-oxalate

++++ 3af-oxalate

++++ 3ag-oxalate

+++ 3ah-oxalate

++ 3ai-oxalate

++++ 3aj-oxalate

++++ 3ak-oxalate

+++ 3al-oxalate

+++ 3am-oxalate

+++ 3an-oxalate

++++ 3ao-oxalate

++++ 3ap-oxalate

++++ 3aq-oxalate

+ 3ar-oxalate

++++ 3as-oxalate

++++ Table Legend: −− = data not available + = K_(i) is greater than 1.0μM ++ = K_(i) is 0.5-1.0 μM +++ = K_(i) is 0.1-0.5 μM ++++ = K_(i) isless than 0.1 μM * The corresponding HCl salts of (+/−)-3o, (−)-3o, and(+)-3o were assayed and afforded comparable results to those obtainedwith 3o-oxalate.

OTHER EMBODIMENTS

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure come within known or customary practice within theart to which the invention pertains and may be applied to the essentialfeatures hereinbefore set forth.

All references, patents, patent application publications, and patentapplications cited herein are hereby incorporated by reference to thesame extent as if each of these references, patents, patent applicationpublications, and patent applications were separately incorporated byreference herein.

What is claimed is:
 1. A method of treating an ischemic heart condition or cardiac arrhythmia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula

or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein each a, b, c, d, e, and f is, independently, —CH₂—, —O—, —S—, or a single bond; each R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is, independently: H, lower alkyl, lower alkyl substituted with —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO₂(lower alkyl), lower alkoxyalkyl substituted with —CO₂(lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO₂R₁₀; each R₁₀ is, independently, lower alkyl or lower alkoxyalkyl; R₁₈ is H or CN; and R₁₉ is H, g is a single bond, and R₂₀ is H, wherein at least one of R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is CO₂R₁₀, lower alkyl substituted by —CO₂(lower alkyl), lower alkyl substituted with —CO₂(lower alkoxyalkyl), lower alkoxyalkyl substituted with —CO₂(lower alkyl), or lower alkoxyalkyl substituted with —CO₂(lower alkoxyalkyl).
 2. The method of claim 1, wherein said ischemic heart condition is selected from the group consisting of stable angina, unstable angina and vasospastic angina.
 3. The method of claim 1, wherein said cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
 4. A method of treating an ischemic heart condition or cardiac arrhythmia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable addition salt thereof.
 5. The method of claim 4, wherein said ischemic heart condition is selected from the group consisting of stable angina, unstable angina, and vasospastic angina.
 6. The method of claim 4, wherein said cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
 7. The method of claim 4, wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable addition salt thereof.
 8. The method of claim 7, wherein said ischemic heart condition is selected from the group consisting of stable angina, unstable angina, and vasospastic angina.
 9. The method of claim 7, wherein said cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
 10. The method of claim 7, wherein said compound is

or a pharmaceutically acceptable addition salt thereof.
 11. The method of claim 10, wherein said ischemic heart condition is selected from the group consisting of stable angina, unstable angina, and vasospastic angina.
 12. The method of claim 10, wherein said cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes. 